26 results on '"Spring, David R."'
Search Results
2. A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066.
- Author
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De Fusco C, Brear P, Iegre J, Georgiou KH, Sore HF, Hyvönen M, and Spring DR
- Subjects
- Binding Sites drug effects, Biphenyl Compounds chemical synthesis, Biphenyl Compounds chemistry, Casein Kinase II antagonists & inhibitors, Casein Kinase II metabolism, Crystallography, X-Ray, Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Biphenyl Compounds pharmacology, Drug Discovery, Protein Kinase Inhibitors pharmacology
- Abstract
Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors., (Copyright © 2017. Published by Elsevier Ltd.)
- Published
- 2017
- Full Text
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3. C-H activation: Complex peptides made simple.
- Author
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Bartlett S and Spring DR
- Subjects
- Carbon chemistry, Catalysis, Hydrogen chemistry, Hydroxyproline chemistry, Oxidation-Reduction, Peptides chemistry, Small Molecule Libraries chemistry, Drug Discovery methods, Iron chemistry, Macrocyclic Compounds chemistry, Peptides chemical synthesis
- Published
- 2016
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4. Studies towards the synthesis of indolizin-5(3H)-one derivatives and related 6,5-azabicyclic scaffolds by ring-closing metathesis.
- Author
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Frei MS, Bilyard MK, Alanine TA, Galloway WR, Stokes JE, and Spring DR
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- Molecular Structure, Aza Compounds chemical synthesis, Bridged Bicyclo Compounds chemical synthesis, Cycloaddition Reaction, Drug Discovery, Indolizines chemical synthesis
- Abstract
Herein, we report on work towards the development of a new strategy for the synthesis of rare and biologically interesting indolizin-5(3H)-ones, which is based around the use of ring-closing metathesis to construct the carbocyclic ring system. This study has provided insights into the general stability of indolizin-5(3H)-ones and their tendency to exist as the tautomeric indolizin-5-ols. Furthermore, this approach has allowed access to other novel structurally related compounds based around unusual 6,5-azabicyclic scaffolds, which are also difficult to generate using typical methods. The azabicyclic compounds synthesized in this study reside in attractive regions of heterocyclic chemical space that are underexploited in current drug and agrochemical discovery efforts., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
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5. How diverse are diversity assessment methods? A comparative analysis and benchmarking of molecular descriptor space.
- Author
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Koutsoukas A, Paricharak S, Galloway WR, Spring DR, Ijzerman AP, Glen RC, Marcus D, and Bender A
- Subjects
- Algorithms, Bayes Theorem, Computational Biology, Computer Simulation, Databases, Chemical, Databases, Pharmaceutical, Drug Discovery statistics & numerical data, Drug Evaluation, Preclinical, Humans, Molecular Structure, Principal Component Analysis, Drug Discovery methods, Models, Chemical
- Abstract
Chemical diversity is a widely applied approach to select structurally diverse subsets of molecules, often with the objective of maximizing the number of hits in biological screening. While many methods exist in the area, few systematic comparisons using current descriptors in particular with the objective of assessing diversity in bioactivity space have been published, and this shortage is what the current study is aiming to address. In this work, 13 widely used molecular descriptors were compared, including fingerprint-based descriptors (ECFP4, FCFP4, MACCS keys), pharmacophore-based descriptors (TAT, TAD, TGT, TGD, GpiDAPH3), shape-based descriptors (rapid overlay of chemical structures (ROCS) and principal moments of inertia (PMI)), a connectivity-matrix-based descriptor (BCUT), physicochemical-property-based descriptors (prop2D), and a more recently introduced molecular descriptor type (namely, "Bayes Affinity Fingerprints"). We assessed both the similar behavior of the descriptors in assessing the diversity of chemical libraries, and their ability to select compounds from libraries that are diverse in bioactivity space, which is a property of much practical relevance in screening library design. This is particularly evident, given that many future targets to be screened are not known in advance, but that the library should still maximize the likelihood of containing bioactive matter also for future screening campaigns. Overall, our results showed that descriptors based on atom topology (i.e., fingerprint-based descriptors and pharmacophore-based descriptors) correlate well in rank-ordering compounds, both within and between descriptor types. On the other hand, shape-based descriptors such as ROCS and PMI showed weak correlation with the other descriptors utilized in this study, demonstrating significantly different behavior. We then applied eight of the molecular descriptors compared in this study to sample a diverse subset of sample compounds (4%) from an initial population of 2587 compounds, covering the 25 largest human activity classes from ChEMBL and measured the coverage of activity classes by the subsets. Here, it was found that "Bayes Affinity Fingerprints" achieved an average coverage of 92% of activity classes. Using the descriptors ECFP4, GpiDAPH3, TGT, and random sampling, 91%, 84%, 84%, and 84% of the activity classes were represented in the selected compounds respectively, followed by BCUT, prop2D, MACCS, and PMI (in order of decreasing performance). In addition, we were able to show that there is no visible correlation between compound diversity in PMI space and in bioactivity space, despite frequent utilization of PMI plots to this end. To summarize, in this work, we assessed which descriptors select compounds with high coverage of bioactivity space, and can hence be used for diverse compound selection for biological screening. In cases where multiple descriptors are to be used for diversity selection, this work describes which descriptors behave complementarily, and can hence be used jointly to focus on different aspects of diversity in chemical space.
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- 2014
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6. Combating multidrug-resistant bacteria: current strategies for the discovery of novel antibacterials.
- Author
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O'Connell KM, Hodgkinson JT, Sore HF, Welch M, Salmond GP, and Spring DR
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- Amino Acid Sequence, Animals, Bacteria chemistry, Bacteria genetics, Bacterial Infections microbiology, Bacteriocins chemistry, Bacteriocins pharmacology, Biological Products chemistry, Biological Products pharmacology, Humans, Metagenome, Molecular Sequence Data, Quorum Sensing drug effects, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Bacteria drug effects, Bacterial Infections drug therapy, Drug Discovery methods, Drug Resistance, Multiple, Bacterial
- Abstract
The introduction of effective antibacterial therapies for infectious diseases in the mid-20th century completely revolutionized clinical practices and helped to facilitate the development of modern medicine. Many potentially life-threatening conditions became easily curable, greatly reducing the incidence of death or disability resulting from bacterial infections. This overwhelming historical success makes it very difficult to imagine life without effective antibacterials; however, the inexorable rise of antibiotic resistance has made this a very real and disturbing possibility for some infections. The ruthless selection for resistant bacteria, coupled with insufficient investment in antibacterial research, has led to a steady decline in the efficacy of existing therapies and a paucity of novel structural classes with which to replace them, or complement their use. This situation has resulted in a very pressing need for the discovery of novel antibiotics and treatment strategies, the development of which is likely to be a key challenge to 21st century medicinal chemistry., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2013
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7. A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling.
- Author
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Beckmann HS, Nie F, Hagerman CE, Johansson H, Tan YS, Wilcke D, and Spring DR
- Subjects
- Molecular Structure, Drug Discovery, Macrocyclic Compounds chemistry, Small Molecule Libraries
- Abstract
A prerequisite for successful screening campaigns in drug discovery or chemical genetics is the availability of structurally and thus functionally diverse compound libraries. Diversity-oriented synthesis (DOS) provides strategies for the generation of such libraries, of which the build/couple/pair (B/C/P) algorithm is the most frequently used. We have developed an advanced B/C/P strategy that incorporates multidimensional coupling. In this approach, structural diversity is not only defined by the nature of the building blocks employed, but also by the linking motif installed during the coupling reaction. We applied this step-efficient approach in a DOS of a library that consisted of 73 macrocyclic compounds based around 59 discrete scaffolds. The macrocycles prepared cover a broad range of different molecular shapes, as illustrated by principal moment-of-inertia analysis. This demonstrates the capability of the advanced B/C/P strategy using multidimensional coupling for the preparation of structurally diverse compound collections.
- Published
- 2013
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8. Diversity-oriented synthesis: producing chemical tools for dissecting biology.
- Author
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O' Connor CJ, Beckmann HS, and Spring DR
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- Animals, Humans, Mice, Models, Molecular, Pharmaceutical Preparations chemistry, Proteins chemistry, Biochemistry methods, Drug Discovery methods, Models, Biological, Small Molecule Libraries
- Abstract
Small molecule modulators of biological function can be discovered by the screening of compound libraries. However, it became apparent that some human disease related targets could not be addressed by the libraries commonly used which typically are comprised of large numbers of structurally similar compounds. The last decade has seen a paradigm shift in library construction, with particular emphasis now being placed on increasing a library's structural, and thus functional diversity, rather than only its size. Diversity-oriented synthesis (DOS) aims to generate such structural diversity efficiently. This tutorial review has been written to introduce the subject to a broad audience and recent achievements in both the preparation and the screening of structurally diverse compound collections against so-called 'undruggable' targets are highlighted.
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- 2012
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9. Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules.
- Author
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Galloway WR, Isidro-Llobet A, and Spring DR
- Subjects
- Molecular Structure, Small Molecule Libraries, Combinatorial Chemistry Techniques methods, Drug Discovery methods
- Abstract
Biologically active molecules can be identified through the screening of small-molecule libraries. Deficiencies in current compound collections are evidenced by the continuing decline in drug-discovery successes. Typically, such collections are comprised of large numbers of structurally similar compounds. A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and thus function, is crucial. Diversity-oriented synthesis (DOS) aims to generate such structural diversity in an efficient manner. Recent years have witnessed significant achievements in the field, which help to validate the usefulness of DOS as a tool for the discovery of novel, biologically interesting small molecules.
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- 2010
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10. The discovery of antibacterial agents using diversity-oriented synthesis.
- Author
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Galloway WR, Bender A, Welch M, and Spring DR
- Subjects
- Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Combinatorial Chemistry Techniques, Drug Evaluation, Preclinical, Genetics, Small Molecule Libraries chemical synthesis, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Anti-Bacterial Agents chemical synthesis, Drug Discovery methods
- Abstract
The emergence and increasing prevalence of multi-drug resistance bacterial strains represents a clear and present danger to the standard of human healthcare as we know it. The systematic study of modulating biological systems using small molecules (so-called chemical genetics) offers a potentially fruitful means of discovering critically needed new antibacterial agents. Crucial to the success of this approach is the ready availability of functionally diverse small molecule collections. In this feature article we focus upon the use of a diversity-oriented synthesis (DOS) approach for the efficient generation of such compound collections, and discuss the utility of DOS for the discovery of new antibacterial agents.
- Published
- 2009
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11. Finding New Components of the Target of Rapamycin (TOR) Signaling Network through Chemical Genetics and Proteome Chips
- Author
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Huang, Jing, Zhu, Heng, Haggarty, Stephen J., Spring, David R., Hwang, Heejun, Jin, Fulai, Snyder, Michael, and Schreiber, Stuart L.
- Published
- 2004
12. Hybrid Androgen Receptor Inhibitors Outperform Enzalutamide and EPI‐001 in in vitro Models of Prostate Cancer Drug Resistance
- Author
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Nicolescu, Radu Costin Bizga, Maylin, Zoe R, Pérez-Areales, Francisco Javier, Iegre, Jessica, Pandha, Hardev S, Asim, Mohammad, Spring, David R, Nicolescu, Radu Costin Bizga [0000-0003-2038-0672], Maylin, Zoe R [0000-0001-6647-213X], Pérez-Areales, Francisco Javier [0000-0001-9525-9346], Iegre, Jessica [0000-0002-9074-653X], Asim, Mohammad [0000-0002-2074-5929], Spring, David R [0000-0001-7355-2824], and Apollo - University of Cambridge Repository
- Subjects
Male ,Pharmacology ,enzalutamide, EPI-001 ,Organic Chemistry ,prostate cancer ,Biochemistry ,Prostatic Neoplasms, Castration-Resistant ,Receptors, Androgen ,Drug Resistance, Neoplasm ,androgen receptor ,Cell Line, Tumor ,Nitriles ,Drug Discovery ,Androgen Receptor Antagonists ,Humans ,Molecular Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,dual inhibitors - Abstract
Funder: Prostate Cancer Foundation; Id: http://dx.doi.org/10.13039/100000892, Funder: UKRI; Id: http://dx.doi.org/10.13039/100014013, Funder: Trinity College Cambridge, Funder: University of Surrey PhD studentship award, Androgen receptor targeted therapies for prostate cancer have serious limitations in advanced stages of the disease. While resistance to the FDA-approved enzalutamide is extensively documented, novel therapies based on epichlorohydrin scaffolds (EPI) are currently in clinical trials, but display suboptimal pharmacokinetics. Herein, we report the synthesis and biological characterisation of a novel class of compounds designed through covalently linking enzalutamide and EPI-001 through various triazole based linkers. The compounds display an 18 to 53 fold improvement in the cell killing potency towards C4-2b prostate cancer (PCa) cells compared to the gold standards of therapy, enzalutamide and EPI-001. The most promising compounds were proven to exhibit their toxicity exclusively through androgen receptor (AR) mediated pathways. This work sets the basis for the first class of hybrid AR inhibitors which successfully combine two drug moieties - EPI-001 and enzalutamide - into the same molecule.
- Published
- 2022
13. Synthesis of Structurally Diverse N-Substituted Quaternary-Carbon-Containing Small Molecules from α,α-Disubstituted Propargyl Amino Esters
- Author
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Mateu, Natalia, Kidd, Sarah L, Kalash, Leen, Sore, Hannah F, Madin, Andrew, Bender, Andreas, Spring, David R, Mateu, Natalia [0000-0001-9451-0666], Spring, David R [0000-0001-7355-2824], and Apollo - University of Cambridge Repository
- Subjects
molecular diversity ,medicinal chemistry ,quaternary stereocenters ,diversity-oriented synthesis ,human activities ,drug discovery - Abstract
N-containing quaternary stereocenters represent important motifs in medicinal chemistry. However, due to their inherently sterically hindered nature, they remain underrepresented in small molecule screening collections. As such, the development of synthetic routes to generate small molecules that incorporate this particular feature are highly desirable. Herein, we describe the diversity-oriented synthesis (DOS) of a diverse collection of structurally distinct small molecules featuring this three-dimensional (3D) motif. The subsequent derivatisation and the stereoselective synthesis exemplified the versatility of this strategy for drug discovery and library enrichment. Chemoinformatic analysis revealed the enhanced sp3 character of the target library and demonstrated that it represents an attractive collection of biologically diverse small molecules with high scaffold diversity.
- Published
- 2018
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14. Partially Saturated Bicyclic Heteroaromatics as an sp3‐Enriched Fragment Collection
- Author
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Twigg, David G., Kondo, Noriyasu, Mitchell, Sophie L., Galloway, Warren R. J. D., Sore, Hannah F., Madin, Andrew, and Spring, David R.
- Subjects
fused-ring systems ,drug design ,Communication ,Drug Discovery ,synthetic methods ,nitrogen heterocycles ,Communications - Abstract
Fragment‐based lead generation has proven to be an effective means of identifying high‐quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp2‐rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio‐ and stereo‐controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters.
- Published
- 2016
15. Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer.
- Author
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Wu, Yuteng, Sore, Hannah F., Spring, David R., Wiedmann, Mareike M., Brenton, James D., Tan, Yaw Sing, Verma, Chandra S., Aibara, Shintaro, Stewart, Murray, Xu, Wenshu, and Itzhaki, Laura
- Subjects
PEPTIDES ,PROTEIN-protein interactions ,OVARIAN cancer ,RENAL cell carcinoma ,CANCER chemotherapy - Abstract
There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1β, in five high- and low-HNF1β-expressing CCC lines. To inhibit the protein function, cell-permeable, non-helical constrained proteomimetics to target the HNF1β-importin α protein-protein interaction were designed, guided by X-ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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16. Partially Saturated Bicyclic Heteroaromatics as an sp3-Enriched Fragment Collection.
- Author
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Twigg, David G., Kondo, Noriyasu, Mitchell, Sophie L., Galloway, Warren R. J. D., Sore, Hannah F., Madin, Andrew, and Spring, David R.
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BICYCLIC compounds ,AROMATIC compounds ,LEAD compounds ,STEREOCHEMISTRY ,DRUG design - Abstract
Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp
2 -rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters. [ABSTRACT FROM AUTHOR]- Published
- 2016
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17. Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips.
- Author
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Jing Huang, Heng Zhu, Haggarty, Stephen J., Spring, David R., Heejun Hwang, Fulai Jin, Snyder, Michael, and Schreiber, Stuart L.
- Subjects
RAPAMYCIN ,MACROLIDE antibiotics ,EUKARYOTIC cells ,GENETICS ,PHOSPHATASES ,ESTERASES - Abstract
The TOR (target of rapamycin) proteins play important roles in nutrient signaling in eukaryotic cells. Rapamycin treatment induces a state reminiscent of the nutrient starvation response, often resulting in growth inhibition. Using a chemical genetic modifier screen, we identified two classes of small molecules, small-molecule inhibitors of rapamycin (SMIRs) and small-molecule enhancers of rapamycin (SMERs), that suppress and augment respectively, rapamycin's effect in the yeast Saccharomyces cerevisiae. Probing proteome chips with biotinylated SMIRs revealed putative intracellular target proteins, including Tep1p, a homolog of the mammalian PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor, and Ybr077cp (Nir1p), a protein of previously unknown function that we show to be a component of the TOR signaling network. Both SMIR target proteins are associated with PI(3,4)P², suggesting a mechanism of regulation of the TOR pathway involving phosphatidylinositides. Our results illustrate the combined use of chemical genetics and proteomics in biological discovery and map a path for creating useful therapeutics for treating human diseases involving the TOR pathway, such as diabetes and cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
18. Synthesis of structurally diverse N-substituted quaternary carbon containing small molecules and their application as novel starting points for drug discovery
- Author
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Kidd, Sarah Louise and Spring, David R.
- Subjects
Fragment-based drug discovery ,medicinal chemistry ,organic synthesis ,organic methodology ,Diversity-oriented synthesis ,drug discovery ,molecular diversity - Abstract
New bioactive small molecules are urgently required to seed both medicinal chemistry and chemical biology research. Within the two last decades, however, organic synthesis has been identified as a limiting factor in this regard owing to the historically uneven exploration of chemical space. Whilst fragment-based screening has proven a fruitful strategy for identifying novel bioactive small molecules, in a similar vein to high-throughput screening approaches, obstacles within this paradigm have been recognised. This relates to a lack of fragment novelty, the overrepresentation of sp2-rich compounds and the lack of readily accessible exit vectors currently demonstrated by commercial screening collections. Thus, the development of novel screening libraries that address these deficiencies is therefore of significant importance. Moreover, innovative strategies are required to aid the somewhat challenging hit validation phase. In this context, the development of high-throughput platforms to accelerate the synthesis of derivatives could provide the opportunity to lower the economic impact of this process. This thesis seeks to explore how diversity-oriented synthesis can be leveraged to tackle these issues. To populate new areas of fragment space, in the first chapter we utilise an α,α-disubstituted amino alcohol building block to generate 12 novel three-dimensional fragments containing an underrepresented N-substituted quaternary carbon moiety. These molecules ultimately contributed to a screening library of 40 compounds featuring this key motif. Importantly, throughout the library medicinally relevant functionalities and modifiable substituents were installed to enable biological recognition and three-dimensional fragment growth. Finally, cheminformatic analysis demonstrated the broad molecular shape diversity of the library and adherence of the library to commonly adopted guidelines within the field. In addition, the library was also shown to compare favourably with existing commercial collections, exhibiting a higher number of chiral centres, a lower fraction aromatic and an improved molecular shape distribution. In the second chapter, we demonstrate the ability of this library to deliver novel hits against challenging biological targets and facilitate multidirectional fragment growth. To achieve this, state-of-the-art high-throughput X-ray crystallographic fragment screening was conducted, leading to the identification of six hits against three novel biological targets (CFI25, Activin A and Penicillin-binding protein 3). Utilising the modular nature of the synthetic route developed, derivatives of each hit were readily generated interrogating several synthetic exit vectors, including the N-substituted quaternary centre. In turn, these analogues were successfully employed as a hit validation strategy, thus providing novel starting points for drug discovery or chemical probe development. Finally, the third chapter describes investigations toward the coupling of rapid analogue construction with the XChem screening platform to provide a direct structural-binding readout via screening of crude reaction mixtures. In this section, we demonstrate the applicability of this library toward high-throughput derivative synthesis using solid-phase catalysis to generate 78 analogues in less than one week. In addition, these studies formed the basis of preliminary investigations toward the development of methodology to enable click chemistry to be implemented within the crude screening protocol. Together, these findings demonstrate the effective nature of structurally diverse N-substituted quaternary small molecules within a fragment-based screening context. Herein, we demonstrate libraries of this nature can provide novel three-dimensional scaffolds to seed screening campaigns and ultimately deliver novel starting points for drug discovery.
- Published
- 2019
- Full Text
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19. Downfalls of Chemical Probes Acting at the Kinase ATP-Site: CK2 as a Case Study
- Author
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Marko Hyvönen, J. Iegre, David R. Spring, Paul Brear, Eleanor L Atkinson, Elizabeth A Zhabina, Atkinson, Eleanor L. [0000-0003-2498-2486], Iegre, Jessica [0000-0002-9074-653X], Brear, Paul D. [0000-0002-4045-0474], Hyvönen, Marko [0000-0001-8683-4070], Spring, David R. [0000-0001-7355-2824], Apollo - University of Cambridge Repository, Atkinson, Eleanor L [0000-0003-2498-2486], Brear, Paul D [0000-0002-4045-0474], and Spring, David R [0000-0001-7355-2824]
- Subjects
molecular probe ,Coronavirus disease 2019 (COVID-19) ,kinase ,CK2 ,Pharmaceutical Science ,Review ,Computational biology ,Biology ,medicine.disease_cause ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,Adenosine Triphosphate ,0302 clinical medicine ,lcsh:Organic chemistry ,Drug Discovery ,medicine ,Humans ,cancer ,Naphthyridines ,Physical and Theoretical Chemistry ,Binding site ,Casein Kinase II ,Protein Kinase Inhibitors ,030304 developmental biology ,Coronavirus ,chemistry.chemical_classification ,0303 health sciences ,Binding Sites ,Kinase ,Organic Chemistry ,Polyphenols ,COVID-19 ,inhibitor ,Enzyme ,Drug development ,chemistry ,Chemistry (miscellaneous) ,Molecular Probes ,030220 oncology & carcinogenesis ,Phenazines ,Molecular Medicine ,Identification (biology) ,Molecular probe ,ATP-site ,Protein Kinases ,Dichlororibofuranosylbenzimidazole - Abstract
Protein kinases are a large class of enzymes with numerous biological roles and many have been implicated in a vast array of diseases, including cancer and the novel coronavirus infection COVID-19. Thus, the development of chemical probes to selectively target each kinase is of great interest. Inhibition of protein kinases with ATP-competitive inhibitors has historically been the most widely used method. However, due to the highly conserved structures of ATP-sites, the identification of truly selective chemical probes is challenging. In this review, we use the Ser/Thr kinase CK2 as an example to highlight the historical challenges in effective and selective chemical probe development, alongside recent advances in the field and alternative strategies aiming to overcome these problems. The methods utilised for CK2 can be applied to an array of protein kinases to aid in the discovery of chemical probes to further understand each kinase’s biology, with wide-reaching implications for drug development.
- Published
- 2021
20. Identification of macrocyclic peptides which activate bacterial cylindrical proteases
- Author
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Raoul Walther, Linda M. Westermann, Sheiliza Carmali, Sophie E. Jackson, Heike Brötz-Oesterhelt, David R. Spring, Walther, Raoul [0000-0002-9833-6703], Carmali, Sheiliza [0000-0003-3436-4745], Brötz-Oesterhelt, Heike [0000-0001-9364-1832], Spring, David R [0000-0001-7355-2824], and Apollo - University of Cambridge Repository
- Subjects
Pharmacology ,Emerging Infectious Diseases ,34 Chemical Sciences ,Organic Chemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,3405 Organic Chemistry ,3404 Medicinal and Biomolecular Chemistry ,Infection ,Biochemistry - Abstract
The caseinolytic protease complex ClpXP is an important house-keeping enzyme in prokaryotes charged with the removal and degradation of misfolded and aggregated proteins and performing regulatory proteolysis. Dysregulation of its function, particularly by inhibition or allosteric activation of the proteolytic core ClpP, has proven to be a promising strategy to reduce virulence and eradicate persistent bacterial infections. Here, we report a rational drug-design approach to identify macrocyclic peptides which increase proteolysis by ClpP. This work expands the understanding of ClpP dynamics and sheds light on the conformational control exerted by its binding partner, the chaperone ClpX, by means of a chemical approach. The identified macrocyclic peptide ligands may, in the future, serve as a starting point for the development of ClpP activators for antibacterial applications.
- Published
- 2023
21. A fragment-based approach leading to the discovery of inhibitors of CK2α with a novel mechanism of action
- Author
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Paul Brear, Claudia De Fusco, Eleanor L. Atkinson, Jessica Iegre, Nicola J. Francis-Newton, Ashok R. Venkitaraman, Marko Hyvönen, David R. Spring, Atkinson, Eleanor L [0000-0003-2498-2486], Iegre, Jessica [0000-0002-9074-653X], Hyvönen, Marko [0000-0001-8683-4070], Spring, David R [0000-0001-7355-2824], and Apollo - University of Cambridge Repository
- Subjects
Pharmacology ,34 Chemical Sciences ,5.1 Pharmaceuticals ,Organic Chemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,3404 Medicinal and Biomolecular Chemistry ,5 Development of treatments and therapeutic interventions ,Biochemistry ,Cancer - Abstract
CK2 is a ubiquitous protein kinase with an anti-apoptotic role and is found to be overexpressed in multiple cancer types. To this end, the inhibition of CK2 is of great interest with regard to the development of novel anti-cancer therapeutics. ATP-site inhibition of CK2 is possible; however, this typically results in poor selectivity due to the highly conserved nature of the catalytic site amongst kinases. An alternative methodology for the modulation of CK2 activity is through allosteric inhibition. The recently identified αD site represents a promising binding site for allosteric inhibition of CK2α. The work presented herein describes the development of a series of CK2α allosteric inhibitors through iterative cycles of X-ray crystallography and enzymatic assays, in addition to both fragment growing and fragment merging design strategies. The lead fragment developed, fragment 8, exhibits a high ligand efficiency, displays no drop off in activity between enzymatic and cellular assays, and successfully engages CK2α in cells. Furthermore, X-ray crystallographic analysis provided indications towards a novel mechanism of allosteric inhibition through αD site binding. Fragments described in this paper therefore represent promising starting points for the development of highly selective allosteric CK2 inhibitors.
- Published
- 2022
22. Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells
- Author
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Sarah L. Kidd, Hannah F. Sore, Hannah R. Bridges, Judy Hirst, David R. Spring, Riccardo Serreli, Thomas J. Osberger, Natalia Mateu, David A. Russell, Russell, David A [0000-0002-2182-4178], Hirst, Judy [0000-0001-8667-6797], Spring, David R [0000-0001-7355-2824], and Apollo - University of Cambridge Repository
- Subjects
Male ,Cell Survival ,Pharmaceutical Science ,Antineoplastic Agents ,Blood–brain barrier ,01 natural sciences ,Article ,Analytical Chemistry ,chemistry.chemical_compound ,Prostate cancer ,Cell Line, Tumor ,Rotenone ,Drug Discovery ,medicine ,Animals ,Humans ,IC50 ,Cell Proliferation ,Pharmacology ,Electron Transport Complex I ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Uncoupling Agents ,Organic Chemistry ,Prostatic Neoplasms ,medicine.disease ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,Complementary and alternative medicine ,Mechanism of action ,Cell culture ,Blood-Brain Barrier ,Mitochondrial Membranes ,Cancer research ,Molecular Medicine ,Cattle ,medicine.symptom ,Drug Screening Assays, Antitumor ,Deguelin ,Cell Division ,Prostate cells - Abstract
Prostate cancer is one of the leading causes of cancer-related death in men. The identification of new therapeutics to selectively target prostate cancer cells is therefore vital. Recently, the rotenoids rotenone (1) and deguelin (2) were reported to selectively kill prostate cancer cells and the inhibition of mitochondrial complex I was established as essential to their mechanism of action. However, these hydrophobic rotenoids readily cross the blood brain barrier and induce symptoms characteristic of Parkinson’s disease in animals. Since hydroxylated derivatives of 1 and 2 are more hydrophilic and less likely to readily cross the blood brain barrier, 29 natural and unnatural hydroxylated derivatives of 1 and 2 were synthesized for evaluation. The inhibitory potency (IC(50)) of each derivative against complex I was measured and its hydrophobicity (Slog(10)P) predicted. Amorphigenin (3), dalpanol (4), dihydroamorphigenin (5), and amorphigenol (6) were selected and evaluated in cell-based assays using C4-2 and C4-2B prostate cancer cells alongside control PNT2 prostate cells. These rotenoids inhibit complex I in cells, decrease oxygen consumption, and selectively inhibit the proliferation of prostate cancer cells, leaving control cells unaffected. The greatest selectivity and anti-proliferative effects were observed with 3 and 5. The data highlight these molecules as promising therapeutic candidates for further evaluation in prostate cancer models.
- Published
- 2020
23. Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion
- Author
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R. Talon, Joseph McLoughlin, Michael Fairhead, Anthony R. Bradley, Dom Bellini, Thomas Armetirding Compton, Katherine McAuley, Paul Brear, Sarah L. Kidd, L. Diaz-Saez, Frank von Delft, T. Krojer, Elaine Fowler, Natalia Mateu, Marko Hyvönen, Christopher G. Dowson, Kilian Huber, A. Aimon, Andrew Madin, Daniel Hillebrand O'donovan, Hector Newman, Hannah F. Sore, Till Reinhardt, David R. Spring, Kidd, Sarah L [0000-0001-9403-8736], Fowler, Elaine [0000-0002-6942-646X], Krojer, Tobias [0000-0003-0661-0814], Aimon, Anthony [0000-0002-9135-129X], Brear, Paul [0000-0002-4045-0474], O'Donovan, Daniel H [0000-0002-8400-2198], Huber, Kilian V M [0000-0002-1103-5300], Hyvönen, Marko [0000-0001-8683-4070], von Delft, Frank [0000-0003-0378-0017], Dowson, Christopher G [0000-0002-8294-8836], Spring, David R [0000-0001-7355-2824], Apollo - University of Cambridge Repository, and Huber, Kilian VM [0000-0002-1103-5300]
- Subjects
0303 health sciences ,34 Chemical Sciences ,010405 organic chemistry ,Computer science ,Drug discovery ,General Chemistry ,Limiting ,Computational biology ,01 natural sciences ,0104 chemical sciences ,03 medical and health sciences ,Chemistry ,1.3 Chemical and physical sciences ,Fragment (logic) ,5.1 Pharmaceuticals ,1 Underpinning research ,QD ,3404 Medicinal and Biomolecular Chemistry ,5 Development of treatments and therapeutic interventions ,030304 developmental biology - Abstract
Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10–14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery., Fragment-based screening of a shape-diverse collection yielded four hits against three proteins. Up to 14 analogues of each hit were rapidly generated, enabling four fragment growth vectors to be explored using inexpensive materials and reliable synthetic transformations.
- Published
- 2020
24. Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery
- Author
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Kim T. Mortensen, Thomas A. King, Hannah L. Stewart, David R. Spring, Andrew J. P. North, Hannah F. Sore, King, Thomas A [0000-0001-6992-8016], Stewart, Hannah L [0000-0002-7891-2590], Sore, Hannah F [0000-0002-6542-0394], Spring, David R [0000-0001-7355-2824], and Apollo - University of Cambridge Repository
- Subjects
010405 organic chemistry ,business.industry ,Drug discovery ,Chemistry ,Communication ,Organic Chemistry ,Fragment-based lead discovery ,Heterocyclic Spirocycles ,Heterocycles ,Diversity‐oriented synthesis ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Cycloaddition ,Communications ,0104 chemical sciences ,Fragment (logic) ,Fragment‐based drug discovery ,Physical and Theoretical Chemistry ,business ,Spirocycles ,Pharmaceutical industry - Abstract
In recent years the pharmaceutical industry has benefited from the advances made in fragment-based drug discovery (FBDD) with more than 30 fragment-derived drugs currently marketed or progressing through clinical trials. The success of fragment-based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp2-rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three-dimensional scaffolds. Herein, we report step-efficient routes to a number of biologically relevant, fragment-like heterocyclic spirocycles. The use of both electron-deficient and electron-rich 2-atom donors was explored in complexity-generating [3+2]-cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses.
- Published
- 2019
25. Using Peptidomimetics and Constrained Peptides as Valuable Tools for Inhibiting Protein–Protein Interactions
- Author
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David R. Spring, Naomi Robertson, Robertson, Naomi S [0000-0001-5519-9158], Spring, David R [0000-0001-7355-2824], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Peptidomimetic ,Pharmaceutical Science ,Computational biology ,Review ,protein–protein interactions ,stapled peptides ,010402 general chemistry ,01 natural sciences ,Analytical Chemistry ,Protein–protein interaction ,lcsh:QD241-441 ,03 medical and health sciences ,Molecular recognition ,lcsh:Organic chemistry ,Drug Discovery ,Physical and Theoretical Chemistry ,Chemistry ,Organic Chemistry ,proteomimetics ,Small molecule ,0104 chemical sciences ,030104 developmental biology ,macrocycles ,Chemistry (miscellaneous) ,peptidomimetics ,Molecular Medicine ,Peptides ,Function (biology) ,Protein Binding - Abstract
Protein–protein interactions (PPIs) are tremendously important for the function of many biological processes. However, because of the structure of many protein–protein interfaces (flat, featureless and relatively large), they have largely been overlooked as potential drug targets. In this review, we highlight the current tools used to study the molecular recognition of PPIs through the use of different peptidomimetics, from small molecules and scaffolds to peptides. Then, we focus on constrained peptides, and in particular, ways to constrain α-helices through stapling using both one- and two-component techniques.
- Published
- 2018
26. Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer
- Author
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Mareike M. Wiedmann, Yaw Sing Tan, Yuteng Wu, Shintaro Aibara, Wenshu Xu, Hannah F. Sore, Chandra S. Verma, Laura Itzhaki, Murray Stewart, James D. Brenton, David R. Spring, Wiedmann, Mareike M [0000-0002-4728-7155], Tan, Yaw Sing [0000-0002-2522-9421], Aibara, Shintaro [0000-0003-2221-482X], Sore, Hannah F [0000-0002-6542-0394], Itzhaki, Laura [0000-0001-6504-2576], Brenton, James D [0000-0002-5738-6683], Spring, David R [0000-0001-7355-2824], Apollo - University of Cambridge Repository, Sore, Hannah [0000-0002-6542-0394], Brenton, James [0000-0002-5738-6683], and Spring, David [0000-0001-7355-2824]
- Subjects
0301 basic medicine ,Models, Molecular ,education ,Konformativ festgelegte Peptide ,Cell-Penetrating Peptides ,Molecular Dynamics Simulation ,010402 general chemistry ,Crystallography, X-Ray ,01 natural sciences ,drug discovery ,Peptidische Wirkstoffe ,03 medical and health sciences ,Wirkstoffentwicklung ,Humans ,health care economics and organizations ,Zellkern-Import ,Ovarian Neoplasms ,peptide therapeutics ,Molecular Structure ,Peptidmimetika ,General Medicine ,constrained peptides ,nuclear import ,0104 chemical sciences ,030104 developmental biology ,peptidomimetics ,Female ,Protein Binding - Abstract
There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1β, in five high- and low-HNF1β-expressing CCC lines. To inhibit the protein function, cell-permeable, non-helical constrained proteomimetics to target the HNF1β–importin α protein–protein interaction were designed, guided by X-ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors.
- Published
- 2017
- Full Text
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