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Summary: Telomerase comprises a reverse transcriptase and an internal RNA template that maintains telomeres in many eukaryotes, and it is a well-validated cancer target. However, there is a dearth of small molecules with efficacy against human telomerase in vivo. We developed a surrogate yeast high-throughput assay to identify human telomerase inhibitors. The reversibility of growth arrest induced by active human telomerase was assessed against a library of 678 compounds preselected for bioactivity in S. cerevisiae. Four of eight compounds identified reproducibly restored growth to strains expressing active human telomerase, and three of these four compounds also specifically inhibited purified human telomerase in vitro. These compounds represent probes for human telomerase function, and potential entry points for development of lead compounds against telomerase-positive cancers. [Copyright &y& Elsevier]

Abstract: Variation at the 3’ position of fluorescein via Suzuki–Miyaura cross-coupling with aryl and heteroaryl moieties gave a family of anthofluoresceins whose spectroscopic properties were studied. The 1-methylindole derivative gave the highest quantum yield and was observed to behave as a molecular rotor, displaying marked variations in fluorescent intensities with viscosity and offering possible application in cellular sensing and fluorescent polarisation assays. [Copyright &y& Elsevier]

Nucleic acids are the foundation stone of all cellular processes. Consequently, the use of DNA or RNA to treat genetic and acquired disorders (so called gene therapy) offers enormous potential benefits. The restitution of defective genes or the suppression of malignant genes could target a range of diseases, including cancers, inherited diseases (cystic fibrosis, muscular dystrophy, etc.), and viral infections. However, this strategy has a major barrier: the size and charge of nucleic acids largely restricts their transit into eukaryotic cells. Potential strategies to solve this problem include the use of a variety of natural and synthetic nucleic acid carriers. Driven by the aim and ambition of translating this promising therapeutic approach into the clinic, researchers have been actively developing advanced delivery systems for nucleic acids for more than 20 years. A decade ago we began our investigations of solid-phase techniques to construct families of novel nucleic acid carriers for transfection. We envisaged that the solid-phase synthesis of polycationic dendrimers and derivatized polyamimes would offer distinct advantages over solution phase techniques. Notably in solid phase synthesis we could take advantage of mass action and streamlined purification procedures, while simplifying the handling of compounds with high polarities and plurality of functional groups. Parallel synthesis methods would also allow rapid access to libraries of compounds with improved purities and yields over comparable solution methodologies and facilitate the development of structure activity relationships. We also twisted the concept of the solid-phase support on its head: we devised miniaturized solid supports that provided an innovative cell delivery vehicle in their own right, carrying covalently conjugated cargos (biomolecules) into cells. In this Account, we summarize the main outcomes of this series of chemically related projects. [ABSTRACT FROM AUTHOR]

Many important intracellular biochemical reactions are modulated by transition metals, typically in the form of metalloproteins. The ability to carry out selective transformations inside a cell would allow researchers to manipulate or interrogate innumerable biological processes. Here, we show that palladium nanoparticles trapped within polystyrene microspheres can enter cells and mediate a variety of Pd0-catalysed reactions, such as allylcarbamate cleavage and Suzuki-Miyaura cross-coupling. The work provides the basis for the customization of heterogeneous unnatural catalysts as tools to carry out artificial chemistries within cells. Such in cellulo synthesis has potential for a plethora of applications ranging from cellular labelling to synthesis of modulators or inhibitors of cell function. [ABSTRACT FROM AUTHOR]

Abstract: The search for novel, generally applicable and highly efficient delivery tools is a major activity in the biotechnology arena. Using highly optimized microwave based solid-phase chemistry a series of fluorescein-labelled cationic peptoid conjugates were synthesized within 24h and cellular uptake into HeLa, L929 and K562 cells examined via flow cytometry. As expected, analysis revealed that longer oligomers achieved greater cellular penetration (7e (9 mer)> 7d (7 mer)> 7c (5 mer)> 7b (3 mer)> 7a (1 mer)) with the nonamer 7e proving to be a remarkable vehicle for all the cell lines, showing excellent penetrability into K562 and L929 cells and extraordinary cell delivery into HeLa cells. Confocal microscopy showed that the hybrid peptoid-nuclear localizing sequence (PKKKRKV from the simian virus 40 large T antigen) resulted in very high levels of nuclei delivery after 3h, opening up a range of applications such as nuclei staining of living cells with non-DNA-intercalating fluorescent probes. [Copyright &y& Elsevier]

Abstract: The synthesis and characterization of five different 9-alkyl-6-amino[1,2,3]triazolo[3,4-c]-5-azaquinoxalines is described. Due to the notable electrophilic character of the C-6 position of the [1,2,4]triazolo[3,4-c]-5-azaquinoxaline tricyclic system, SNAr amination was achieved simply by reacting the corresponding 6-chloro derivative with ammonia-saturated acetonitrile (a non-nucleophilic polar solvent) in a sealed reaction vessel, using microwave-mediated or conventional heating. [Copyright &y& Elsevier]

Abstract: A new multicolor pH-dependent fluorophore was synthesized via Pd-mediated cross-coupling chemistry of the mono-triflate of fluorescein with p-hydroxyphenylboronic acid. The novel indicator, named anthofluorescein, is highly sensitive to pH changes between 7 and 10 and displays a green to red fluorescence shift, making it a valuable candidate for biological studies. [Copyright &y& Elsevier]

The one-pot synthesis of new 9-alkyl-6-chloropyrido [3 ,2-e] - [1,2,4]triazolo[4,3-α]pyrazines has been achieved. Hydrazides regios electively reacted as nucleophiles with the 3-chloro substituent of 2,3 -dichloropyrido [2, 3-bI pyrazine. An intramolecular cyclization afforded the tricycle nonxanthine adenosine receptor antagonists. [ABSTRACT FROM AUTHOR]

NXP900 is a selective and potent SRC family kinase (SFK) inhibitor, currently being dosed in a phase 1 clinical trial, that locks SRC in the “closed” conformation, thereby inhibiting both kinase-dependent catalytic activity and kinaseindependent functions. In contrast, several multi-targeted kinase inhibitors that inhibit SRC, including dasatinib and bosutinib, bind their target in the active “open” conformation, allowing SRC and other SFKs to act as a scaffold to promote tumorigenesis through non-catalytic functions. NXP900 exhibits a unique target selectivity profile with sub-nanomolar activity against SFK members over other kinases. This results in highly potent and specific SFK pathway inhibition. Here, we demonstrate that esophageal squamous cell carcinomas and head and neck squamous cell carcinomas are exquisitely sensitive to NXP900 treatment in cell culture and in vivo, and we identify a patient population that could benefit from treatment with NXP900. [ABSTRACT FROM AUTHOR]

Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies. We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines. 16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy. Dasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation. • We performed a high throughput screen of 1610 compounds across six low grade serous ovarian carcinoma cell lines • Of 16 prioritised screen hits, 11 compounds passed dose-response validation using cell viability assays • The most promising hits underwent synergy profiling with the trametinib (dasatinib, disulfiram, carfilzomib, romidepsin) • Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines • Dasatinib demonstrated favourable synergy with the MEK inhibitor trametinib [ABSTRACT FROM AUTHOR]

Transition‐metal‐catalyzed bioorthogonal reactions emerged a decade ago as a novel strategy to implement spatiotemporal control over enzymatic functions and pharmacological interventions. The use of this methodology in experimental therapy is driven by the ambition of improving the tolerability and PK properties of clinically‐used therapeutic agents. The preclinical potential of bioorthogonal catalysis has been validated in vitro and in vivo with the in situ generation of a broad range of drugs, including cytotoxic agents, anti‐inflammatory drugs and anxiolytics. In this article, we report our investigations towards the preparation of solid‐supported Cu(I)‐microdevices and their application in bioorthogonal uncaging and click reactions. A range of ligand‐functionalized polymeric devices and off‐on Cu(I)‐sensitive sensors were developed and tested under conditions compatible with life. Last, we present a preliminary exploration of their use for the synthesis of PROTACs through CuAAC assembly of two heterofunctional mating units. [ABSTRACT FROM AUTHOR]

The incorporation of abiotic transition metal catalysis into the chemical biology space has significantly expanded the tool kit of bioorthogonal chemistries accessible for cell culture and in vivo applications. A rich variety of homogeneous and heterogeneous catalysts has shown functional compatibility with physiological conditions and biostability in complex environs, enabling their exploitation as extracellular or intracellular factories of bioactive agents. Current trends in the field are focusing on investigating new metals and sophisticated catalytic devices and toward more applied activities, such as the integration of subcellular, cell- and site-targeting capabilities or the exploration of novel biomedical applications. We present herein an overview of the latest advances in the field, highlighting the increasing role of transition metals for the controlled release of therapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

The article focuses on the study conducted by Rotello and colleagues which describes a nanorobot combining non-biological catalytic system with artificial regulatory elements. Topics include the biocompatibility of the nanorobot, the capability of a Pd catalyst-containing device in the intracellular activation of prodrugs, and the potential benefits of integrating bioorthogonal catalysts and mechanochemical components into artificial nanostructures.

Several studies have reported the successful use of bio-orthogonal catalyst nanoparticles (NPs) for cancer therapy. However, the delivery of the catalysts to the target tissues in vivo remains an unsolved challenge. The combination of catalytic NPs with extracellular vesicles (EVs) has been proposed as a promising approach to improve the delivery of therapeutic nanomaterials to the desired organs. In this study, we have developed a nanoscale bio-hybrid vector using a CO-mediated reduction at low temperature to generate ultrathin catalytic Pd nanosheets (PdNSs) as catalysts directly inside cancer-derived EVs. We have also compared their biodistribution with that of PEGylated PdNSs delivered by the EPR effect. Our results indicate that the accumulation of PdNSs in the tumour tissue was significantly higher when they were administered within the EVs compared to the PEGylated PdNSs. Conversely, the amount of Pd found in non-target organs (i.e., liver) was lowered. Once the Pd-based catalytic EVs were accumulated in the tumours, they enabled the activation of a paclitaxel prodrug demonstrating their ability to carry out bio-orthogonal uncaging chemistries in vivo for cancer therapy. [ABSTRACT FROM AUTHOR]

Bioorthogonal uncaging strategies have recently emerged as an experimental therapeutic approach to control drug release. Herein we report a novel masking strategy that enables to modulate the metal chelating properties of hydroxamic acid groups by bioorthogonal chemistry using Pd-functionalized resins. This novel approach allowed to devise an inactive precursor of the histone deacetylase inhibitor vorinostat that was efficiently uncaged by heterogeneous Pd catalysis in cell culture models of glioma and lung cancer. [ABSTRACT FROM AUTHOR]

Dysregulation of the AXL receptor tyrosine kinase has been associated with many types of cancer. It has not been until recently, however, that targeting AXL has come under the spotlight because of ever accumulating evidence of its strong correlation with poor prognosis and drug resistance. The entry of the first AXL-branded inhibitor in clinical trials in 2013 marked an important milestone for the clinical validation of AXL as an anticancer target. Nevertheless, to weigh the current contribution and potential future impact of AXL inhibition in the clinic, it is fundamental to recognize that several kinase inhibitors approved or in clinical development have AXL as either a prominent secondary or even the primary target. Through this review, the chemical and biological properties of the main inhibitors targeting AXL (either intentionally or unintentionally) will be discussed, along with the prospects and challenges to translate AXL inhibitors into a bona fide therapeutic option. [ABSTRACT FROM AUTHOR]

[Display omitted] Heteromeric T andem pore domain A cid S ensitive (TASK)-1/3 channels are critical to oxygen-sensing by carotid body type 1 cells, where hypoxia-induced inhibition of TASK-3 and/or TASK-1/3 potassium currents leads to voltage-gated calcium entry, exocytotic transmitter release and increases in carotid body afferent input responses that initiate corrective changes in breathing patterns. It was proposed that, in response to hypoxia, the AMP–activated protein kinase (AMPK) might directly phosphorylate and inhibit TASK channels, in particular TASK–3, but studies on rat type I cells questioned this view. However, sequence alignment identified a putative AMPK recognition motif in human (h) TASK-3, but not hTASK–1, with Ser55 representing a potential phosphorylation site. We therefore studied the effects of five different AMPK activators on recombinant hTASK–3 potassium channels expressed in human embryonic kidney (HEK)–293 cells. Two structurally unrelated AMPK activators, the thienopyridine A–769662 (100–500 µM) and the benzimidazole 991 (3–30 µM) inhibited hTASK–3 currents in a concentration–dependent manner, while the 4-azabenzimidazole MK–8722 (3–30 µM) partially inhibited hTASK–3 at concentrations above those required for maximal AMPK activation. By contrast, the 4-azabenzimidazole, BI-9774 (10–100 µM; a closely related analogue of MK8722) and the pro-drug AICA-riboside (1 mM; metabolised to ZMP, an AMP-mimetic) had no significant effect on hTASK–3 currents at concentrations sufficient to maximally activate AMPK. Importantly, A–769662 (300 µM) also inhibited hTASK–3 channel currents in HEK–293 cells that stably over-expressed an AMPK–β1 subunit mutant (S108A) that renders AMPK insensitive to activators that bind to the Allosteric Drug and Metabolite site, such as A–769662. We therefore identify A–769662 and 991 as novel hTASK–3 channel inhibitors and provide conclusive evidence that AMPK does not regulate hTASK–3 channel currents. [ABSTRACT FROM AUTHOR]

Being recognized as the best‐tolerated of all metals, the catalytic potential of gold (Au) has thus far been hindered by the ubiquitous presence of thiols in organisms. Herein we report the development of a truly‐catalytic Au‐polymer composite by assembling ultrasmall Au‐nanoparticles at the protein‐repelling outer layer of a co‐polymer scaffold via electrostatic loading. Illustrating the in vivo‐compatibility of the novel catalysts, we show their capacity to uncage the anxiolytic agent fluoxetine at the central nervous system (CNS) of developing zebrafish, influencing their swim pattern. This bioorthogonal strategy has enabled ‐for the first time‐ modification of cognitive activity by releasing a neuroactive agent directly in the brain of an animal. [ABSTRACT FROM AUTHOR]

Being recognized as the best‐tolerated of all metals, the catalytic potential of gold (Au) has thus far been hindered by the ubiquitous presence of thiols in organisms. Herein we report the development of a truly‐catalytic Au‐polymer composite by assembling ultrasmall Au‐nanoparticles at the protein‐repelling outer layer of a co‐polymer scaffold via electrostatic loading. Illustrating the in vivo‐compatibility of the novel catalysts, we show their capacity to uncage the anxiolytic agent fluoxetine at the central nervous system (CNS) of developing zebrafish, influencing their swim pattern. This bioorthogonal strategy has enabled ‐for the first time‐ modification of cognitive activity by releasing a neuroactive agent directly in the brain of an animal. [ABSTRACT FROM AUTHOR]

The article discusses a study regarding use of extracellular palladium-catalyzed dealkylation of 5-Fluoro- 1-propargyl-uracil (5FU) as bioorthogonally activated prodrug approach for chemotherapy. It mentions that alkylation of 5FU would both suppress the cytotoxic properties of drug and make the prodrug become resistant to enzymatic cleavage. Also it reports that the approach would allow for a reduction in side effects of other chemotherapeutic regimes.

The article says that a team of researchers, led by Dr. Unciti-Broceta, at the Edinburgh Cancer Discovery Unit in Scotland, is using bioorthogonally activated chemotherapy to study whether solid metals can be used as implantable activating devices to modulate the cytotoxic activity of antineoplastic drugs. It says that palladium, a metal which helps in catalyzing various chemical reactions, is used in the new approach.

Novel palladium (Pd)-loaded titanium (Ti) devices with high biocompatibility and catalytic activity were prepared using a range of fabrication methods such as powder metallurgy (i.e. sintering with and without space-holder), sputtering, pulsed laser deposition and supersonic cluster beam deposition. The surface of the Ti-[Pd] devices were physico-chemically characterised to confirm the non-alloyed state of the Pd coating onto the titanium substrate. The Pd thickness was optimised to achieve maximum surface area (i.e. maximum catalytic effect) using the minimum amount of material in each method for cost effective production. The catalytic response of the different Ti-[Pd] devices was evaluated under biocompatible conditions by employing an off–on Pd-activatable fluorescent probe. The most robust coating of Pd was produced by an optimised magnetron sputtering method. The sputtered Ti-[Pd] devices were selected to induce the bioorthogonal uncaging of the anticancer drug Vorinostat from a pharmacologically-inactive Pd-activatable precursor in cancer cell culture, demonstrating the capacity of these devices to mediate a local anti-tumour effect via in situ release of a clinically approved drug. This approach is the first step towards surgically implantable devices that could facilitate targeting affected areas with high spatial selectivity, improving pharmacological activity and reducing systemic side effects through localised treatment directly at the cancer site. [ABSTRACT FROM AUTHOR]

SN‐38, the active metabolite of irinotecan, is released upon liver hydrolysis to mediate potent antitumor activity. Systemic exposure to SN‐38, however, also leads to serious side effects. To reduce systemic toxicity by controlling where and when SN‐38 is generated, a new prodrug was specifically designed to be metabolically stable and undergo rapid palladium‐mediated activation. Blocking the phenolic OH of SN‐38 with a 2,6‐bis(propargyloxy)benzyl group led to significant reduction of cytotoxic activity (up to 44‐fold). Anticancer properties were swiftly restored in the presence of heterogeneous palladium (Pd) catalysts to kill colorectal cancer and glioma cells, proving the efficacy of this novel masking strategy for aromatic hydroxyls. Combination with a Pd‐activated 5FU prodrug augmented the antiproliferative potency of the treatment, while displaying no activity in the absence of the Pd source, which illustrates the benefit of achieving controlled release of multiple approved therapeutics—sequentially or simultaneously—by the same bioorthogonal catalyst to increase anticancer activity. Palladium‐functionalized microdevices were used to uncage newly developed prodrug that releases SN‐38 (irinotecan′s active metabolite) in combination with previously known anticancer prodrug of 5FU. [ABSTRACT FROM AUTHOR]

Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively and is informed by biochemical assays. To drive development toward specific oncopathways, compounds were tested against cancer cells that overexpress, or not, AXL kinase. Identified phenotypic hits were found to inhibit oncotargets AXL, RET, and FLT3. Subsequent optimization generated antiproliferative lead compounds with unique selectivity profiles, including selective AXL inhibitors and a highly potent inhibitor of FLT3. [ABSTRACT FROM AUTHOR]

Recent advances in bioorthogonal catalysis are increasing the capacity of researchers to manipulate the fate of molecules in complex biological systems. A bioorthogonal uncaging strategy is presented, which is triggered by heterogeneous gold catalysis and facilitates the activation of a structurally diverse range of therapeutics in cancer cell culture. Furthermore, this solid-supported catalytic system enabled locally controlled release of a fluorescent dye into the brain of a zebrafish for the first time, offering a novel way to modulate the activity of bioorthogonal reagents in the most fragile and complex organs. [ABSTRACT FROM AUTHOR]

Recent advances in bioorthogonal catalysis are increasing the capacity of researchers to manipulate the fate of molecules in complex biological systems. A bioorthogonal uncaging strategy is presented, which is triggered by heterogeneous gold catalysis and facilitates the activation of a structurally diverse range of therapeutics in cancer cell culture. Furthermore, this solid-supported catalytic system enabled locally controlled release of a fluorescent dye into the brain of a zebrafish for the first time, offering a novel way to modulate the activity of bioorthogonal reagents in the most fragile and complex organs. [ABSTRACT FROM AUTHOR]

Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure-activity relationships that biased subsequent designs toward breast cancer treatment rather than to a particular target. This strategy led to the discovery of two potent antiproliferative leads with phenotypically distinct anticancer mode of actions. Kinase profiling and further optimization resulted in eCF506, the first small molecule with subnanomolar IC50 for SRC that requires 3 orders of magnitude greater concentration to inhibit ABL. eCF506 exhibits excellent water solubility, an optimal DMPK profile and oral bioavailability, halts SRC-associated neuromast migration in zebrafish embryos without inducing life-threatening heart defects, and inhibits SRC phosphorylation in tumor xenografts in mice. [ABSTRACT FROM AUTHOR]

Herein we report the development and biological screening of a bioorthogonal palladium-labile prodrug of the nucleoside analogue floxuridine, a potent antineoplastic drug used in the clinic to treat advanced cancers. N-propargylation of the N3 position of its uracil ring resulted in a vast reduction of its biological activity (~6,250-fold). Cytotoxic properties were bioorthogonally rescued in cancer cell culture by heterogeneous palladium chemistry both in normoxia and hypoxia. Within the same environment, the reported chemo-reversible prodrug exhibited up to 1,450-fold difference of cytotoxicity whether it was in the absence or presence of the extracellular palladium source, underlining the precise modulation of bioactivity enabled by this bioorthogonally-activated prodrug strategy. [ABSTRACT FROM AUTHOR]

Malaria and Chagas disease, caused by Plasmodium spp. and Trypanosoma cruzi parasites, remain important global health problems. Available treatments for those diseases present several limitations, such as lack of efficacy, toxic side effects, and drug resistance. Thus, new drugs are urgently needed. The discovery of new drugs may be benefited by considering the significant biological differences between hosts and parasites. One of the most striking differences is found in the purine metabolism, because most of the parasites are incapable of de novo purine biosynthesis. Herein, we have analyzed the in vitro anti-P. falciparum and anti-T. cruzi activity of a collection of 81 purine derivatives and pyrimidine analogs. We firstly used a primary screening at three fixed concentrations (100, 10, and 1 µM) and progressed those compounds that kept the growth of the parasites < 30% at 100 µM to dose–response assays. Then, we performed two different cytotoxicity assays on Vero cells and human HepG2 cells. Finally, compounds specifically active against T. cruzi were tested against intracellular amastigote forms. Purines 33 (IC50 = 19.19 µM) and 76 (IC50 = 18.27 µM) were the most potent against P. falciparum. On the other hand, 6D (IC50 = 3.78 µM) and 34 (IC50 = 4.24 µM) were identified as hit purines against T. cruzi amastigotes. Moreover, an in silico docking study revealed that P. falciparum and T. cruzi hypoxanthine guanine phosphoribosyltransferase enzymes could be the potential targets of those compounds. Our study identified two novel, purine-based chemotypes that could be further optimized to generate potent and diversified anti-parasitic drugs against both parasites. [ABSTRACT FROM AUTHOR]

[Display omitted] The recent incorporation of Au chemistry in the bioorthogonal toolbox has opened up new opportunities to deliver biologically independent reactions in living environments. Herein we report that the O -propargylation of the hydroxamate group of the potent HDAC inhibitor panobinostat leads to a vast reduction of its anticancer properties (>500-fold). We also show that this novel prodrug is converted back into panobinostat in the presence of Au catalysts in vitro and in cell culture. [ABSTRACT FROM AUTHOR]

Although anti-VEGF therapies have radically changed clinical practice, there is still an urgent demand for novel, integrative approaches for sight-threatening retinal vascular diseases. As we hypothesize that protein tyrosine kinases are key signaling mediators in retinal vascular disease, we performed a comprehensive activity-based tyrosine kinome profiling on retinal tissue of 12-week-old Akimba mice, a translational model displaying hallmarks of early and advanced diabetic retinopathy. Western blotting was used to confirm retinal tyrosine kinase activity in Akimba mice. HUVEC tube formation and murine organotypic choroidal sprouting assays were applied to compare tyrosine kinase inhibitors with different specificity profiles. HUVEC toxicity and proliferation were evaluated using the CellTox™ Green Cytotoxicity and PrestoBlue™ Assays. Our results indicate a shift of the Akimba retinal tyrosine kinome towards a hyperactive state. Functional network analysis of significantly hyperphosphorylated peptides and upstream kinase prediction revealed a central role for Src-FAK family kinases. Western blotting confirmed hyperactivity of this signaling node in the retina of Akimba mice. We demonstrated that not only Src but also FAK family kinase inhibitors with different selectivity profiles were able to suppress angiogenesis in vitro and ex vivo. In the latter model, the novel selective Src family kinase inhibitor eCF506 was able to achieve potent reduction of angiogenesis, comparable to the less specific inhibitor Dasatinib. None of the tested compounds demonstrated acute endothelial cell toxicity. Overall, the collected findings provide the first comprehensive overview of retinal tyrosine kinome changes in the Akimba model of diabetic retinopathy and for the first time highlight Src family kinase inhibition using highly specific inhibitors as an attractive therapeutic intervention for retinal vascular pathology. • Retinal tyrosine kinome profiling reveals hyperactivity in diabetic Akimba mice. • Functional network analysis identifies Src-FAK family kinases as central node. • Specific Src family kinase inhibition potently suppresses ex vivo angiogenesis. [ABSTRACT FROM AUTHOR]

The search for novel targeted inhibitors active on glioblastoma multiforme is crucial to develop new treatments for this unmet clinical need. Herein, we report the results from a screening campaign against glioma cell lines using a proprietary library of 100 structurally-related pyrazolopyrimidines. Data analysis identified a family of compounds featuring a 2-amino-1,3-benzoxazole moiety (eCF309 to eCF334) for their antiproliferative properties in the nM range. These results were validated in patient-derived glioma cells. Available kinase inhibition profile pointed to blockade of the PI3K/mTOR pathway as being responsible for the potent activity of the hits. Combination studies demonstrated synergistic activity by inhibiting both PI3Ks and mTOR with selective inhibitors. Based on the structure activity relationships identified in this study, five new derivatives were synthesized and tested, which exhibited potent activity against glioma cells but not superior to the dual PI3K/mTOR inhibitor and lead compound of the screening eCF324. [ABSTRACT FROM AUTHOR]

Summary 5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1High melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1High cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer. Graphical Abstract Highlights • ALDH1 bio-activates nifuroxazide leading to ALDH1 inactivation and cytotoxicity • Nifuroxazide selectively eradicates ALDH1High melanoma tumor-initiating cells • Targeted therapy increases ALDH1 in some patient melanomas and cell line models • Targeting ALDH1High cells with nifuroxazide is an orthogonal therapeutic strategy A major challenge for cancer treatment is that tumors are comprised of subpopulations with differing growth potential and drug sensitivity. Here, Sarvi and colleagues reveal that the clinically approved antibiotic, nifuroxazide, selectively eliminates ALDH1High melanoma-initiating cell subpopulations. This conceptual advance opens up new avenues in drug repurposing and melanoma therapy. [ABSTRACT FROM AUTHOR]

Systemic side effects limit the efficacy of chemotherapy regimens. To reduce toxicity, a metabolically stable prodrug of SN‐38 (irinotecan's active metabolite) has been designed to be exclusively activated by Pd‐functionalized microdevices that can be implanted into tumors. It is also shown the first concomitant uncaging of two drugs used in clinical combinations by the same bioorthogonal method. More information can be found in the Full Paper by P. M. Brennan, A. Unciti‐Broceta, et al. on page 16783 ff. [ABSTRACT FROM AUTHOR]

Thiole sind allgegenwärtig in lebenden Systemen, und ihre starke Bindung an Goldoberflächen hält andere funktionelle Gruppen fast vollständig von diesen fern. In ihrer Zuschrift auf S. 12727 berichten J. Santamaría, A. Unciti ‐ Broceta et al. über Gold ‐ Heterogenkatalysatoren für die bioorthogonale Aktivierung zugelassener Tumortherapeutika (durch O/N ‐ Depropargylierung) in Krebszellkulturen und die erste Aktivierung einer bioorthogonalen Sonde im Gehirn von Zebrafischen. [ABSTRACT FROM AUTHOR]

Thiols are ubiquitous in living systems where they bind strongly to gold surfaces and render interactions with other functional groups basically non‐existent. In their Communication on page 12548 ff., J. Santamaría and A. Unciti‐Broceta et al. describe heterogeneous gold catalysts that enable bioorthogonal uncaging (by O/N‐depropargylation) of clinically approved anticancer drugs in cancer cell culture, and the first intracranial activation of a bioorthogonal probe in a zebrafish. [ABSTRACT FROM AUTHOR]