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Background: Cockayne syndrome (CS) is a DNA repair disorder primarily associated with pathogenic variants in ERCC6 and ERCC8. As in other Mendelian disorders, there are a number of genetically unsolved CS cases. Methods: We ascertained five individuals with monoallelic pathogenic variants in MORC2, previously associated with three dominantly inherited phenotypes: an axonal form of Charcot-Marie-Tooth disease type 2Z; a syndrome of developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy; and a rare form of spinal muscular atrophy. Results: One of these individuals bore a strong phenotypic resemblance to CS. We then identified monoallelic pathogenic MORC2 variants in three of five genetically unsolved individuals with a clinical diagnosis of CS. In total, we identified eight individuals with MORC2-related disorder, four of whom had clinical features strongly suggestive of CS. Conclusions: Our findings indicate that some forms of MORC2-related disorder have phenotypic similarities to CS, including features of accelerated aging. Unlike classic DNA repair disorders, MORC2-related disorder does not appear to be associated with a defect in transcription-coupled nucleotide excision repair and follows a dominant pattern of inheritance with variants typically arising de novo. Such de novo pathogenic variants present particular challenges with regard to both initial gene discovery and diagnostic evaluations. MORC2 should be included in diagnostic genetic test panels targeting the evaluation of microcephaly and/or suspected DNA repair disorders. Future studies of MORC2 and its protein product, coupled with further phenotypic characterization, will help to optimize the diagnosis, understanding, and therapy of the associated disorders.

To improve our ability to extrapolate preclinical toxicity to humans, there is a need to understand and quantify the concordance of adverse events (AEs) between animal models and clinical studies. In the present work, we discovered 3011 statistically significant associations between preclinical and clinical AEs caused by drugs reported in the PharmaPendium database of which 2952 were new associations between toxicities encoded by different Medical Dictionary for Regulatory Activities terms across species. To find plausible and testable candidate off-target drug activities for the derived associations, we investigated the genetic overlap between the genes linked to both a preclinical and a clinical AE and the protein targets found to interact with one or more drugs causing both AEs. We discuss three associations from the analysis in more detail for which novel candidate off-target drug activities could be identified, namely, the association of preclinical mutagenicity readouts with clinical teratospermia and ovarian failure, the association of preclinical reflexes abnormal with clinical poor-quality sleep, and the association of preclinical psychomotor hyperactivity with clinical drug withdrawal syndrome. Our analysis successfully identified a total of 77% of known safety targets currently tested in in vitro screening panels plus an additional 431 genes which were proposed for investigation as future safety targets for different clinical toxicities. This work provides new translational toxicity relationships beyond AE term-matching, the results of which can be used for risk profiling of future new chemical entities for clinical studies and for the development of future in vitro safety panels.

In this study, we present a fully automatic platform based on our Monte Carlo algorithm, the Protein Energy Landscape Exploration method (PELE), for the estimation of absolute protein-ligand binding free energies, one of the most significant challenges in computer aided drug design. Based on a ligand pathway approach, an initial short enhanced sampling simulation is performed to identify reasonable starting positions for more extended sampling. This stepwise approach allows for a significant faster convergence of the free energy estimation using the Markov State Model (MSM) technique. PELE-MSM was applied on four diverse protein and ligand systems, successfully ranking compounds for two systems. Based on the results, current limitations and challenges with physics-based methods in computational structural biology are discussed. Overall, PELE-MSM constitutes a promising step toward computing absolute binding free energies and in their application into drug discovery projects.

Mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are common oncogenic driver events in non-small cell lung cancer. Although the activation of EGFR in normal cells is primarily driven by growth-factor-binding-induced dimerization, mutations on different exons of the kinase domain of the receptor have been found to affect the equilibrium between its active and inactive conformations giving rise to growth-factor-independent kinase activation. Using molecular dynamics simulations combined with enhanced sampling techniques, we compare here the conformational landscape of the monomers and homodimers of the wild-type and mutated forms of EGFR ΔELREA and L858R, as well as of two exon 20 insertions, D770-N771insNPG, and A763-Y764insFQEA. The differences in the conformational energy landscapes are consistent with multiple mechanisms of action including the regulation of the hinge motion, the stabilization of the dimeric interface, and local unfolding transitions. Overall, a combination of different effects is caused by the mutations and leads to the observed aberrant signaling.

Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

[Image: see text] A series of pyrrolidine amino nitrile DPP1 inhibitors have been developed and characterized. The S2 pocket structure–activity relationship for these compounds shows significant gains in potency for DPP1 from interacting further with target residues and a network of water molecules in the binding pocket. Herein we describe the X-ray crystal structures of several of these compounds alongside an analysis of factors influencing the inhibitory potency toward DPP1 of which stabilization of the water network, demonstrated using Grand Canonical Monte Carlo simulations and free energy calculations, is attributed as a main factor.

Cockayne syndrome (CS) is a rare genetic disorder, characterised by impaired growth and microcephaly, developmental delay and premature pathological ageing. Affected children often develop cataracts, retinal degeneration, hearing loss, muscle weakness and contractures as part of the condition. The mean age at death is 8.4 years. When the authors first met, the Amy and Friends support group was only a few years old, having been established to enable families affected by CS to share and learn from each other’s experiences. Since then, the organisation has grown to be the largest provider of support and advocacy for families affected by CS worldwide, both in person and through social media. Jayne Hughes is founder and chief executive of the organisation and Amy’s mother. Brian Wilson joined the clinicians and scientists already associated with Amy and Friends as a clinical geneticist with a special interest in CS. Here we share some of the lessons we have learnt for effectively working together. Each year, families and professionals from around the world gather for the Amy and Friends family and medical conference. A recurrent concern raised by families was lack of awareness of CS among health professionals. Indeed, some mothers have been berated by clinicians who assumed their child’s problems had been caused by cocaine consumption during pregnancy, not realising that the disorder had been named for Edward Cockayne, the British paediatrician who first reported it in 1936. Families wanted practical information about what to expect for their affected child and how best to care for them. Many also wanted to establish whether issues they had experienced were unique to their child or unreported features of CS. Although almost 500 scientific and clinical papers had been published on CS, many questions could not be answered by the professionals. However, other families were able to respond, …

The bromodomain-containing proteins are a ligandable family of epigenetic readers, which play important roles in oncological, cardiovascular, and inflammatory diseases. Achieving selective inhibition of specific bromodomains is challenging, due to the limited understanding of compound and target selectivity features. In this study we build and benchmark proteochemometric (PCM) classification models on bioactivity data for 15,350 data points across 31 bromodomains, using both compound fingerprints and binding site protein descriptors as input variables, achieving a maximum performance as measured by the Matthew's Correlation Coefficient (MCC) of 0.83 on the external test set. We also find that histone peptide binding data can be used as a target descriptor to build a high performing PCM model (MCC 0.80), showing the transferability of peptide interaction information to modeling small-molecule bioactivity. 1,139 compounds were selected for prospective experimental testing by performing a virtual screen using model predictions and implementing conformal prediction, which resulted in 319 correctly predicted compound-target pair actives and the correct prediction for certain selectivity profile combinations of the four bromodomains tested against. We identify that conformal prediction can be used to fine-tune the balance between hit retrieval and hit structural diversity in a virtual screening setting. PCM can be applied to future virtual screening and compound design, including off-target prediction for bromodomains.

The estrogen receptor alpha (ERα) is expressed in >70% of breast cancers and is a clinically validated target in oncology.1 Anti-hormonal therapies that directly block ER function (e.g., tamoxifen) or therapies that block the production of estrogen itself (e.g., aromatase inhibitors) have proven to be effective treatments of the disease. Further advances have been made with the development of SERDs (Selective Estrogen Receptor Degraders) such as fulvestrant which both antagonise ERα-driven tumor cell growth and cause degradation of the ERα receptor.2 We previously disclosed the identification of a tricyclic indole scaffold that led to the orally active clinical candidate AZD9496.3 Additional work to identify novel chemotypes including phenol 14 and indazole 25 was also disclosed together. The work previously disclosed relied on the presence of the acrylic acid for efficient degradation of the estrogen receptor. In this poster we will discuss the replacement of the acrylic acid on the tricyclic indole scaffold with amines (e.g. compound 3). Compound 3 is a degrader of the estrogen receptor in the MCF-7 cell line (pIC50 8.4). Further optimisation of lead structure 3 led to more potent selective degraders of the estrogen receptor in multiple cell lines (e.g. pIC50 >10 in MCF-7) with suitable properties for oral absorption (e.g. oral AUC 44 μM.h in mice at 20 mg/kg). We will discuss some of the medicinal chemistry challenges that were faced along the way and the optimisation strategy (use of NMR derived solution phase conformations, understanding of the binding mode in the estrogen receptor by X-ray crystallography). ol> Citation Format: Bernard Barlaam, Jason Breed, Rodrigo J Carbajo, Eric Gangl, Samantha Hughes, Christopher J Morrow, Thomas A Moss, Radoslaw Polanski, Willem M Nissink, Daniel O'Donovan, Jeffrey Varnes, Bin Yang, James S Scott. Small Molecule Degraders of the Estrogen Receptor (SERDs): Optimization of the tricyclic indole scaffold beyond AZD9496 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A107. doi:10.1158/1535-7163.TARG-19-A107

This paper reports the psychometric testing of the Worthing Chemotherapy Questionnaire (WCQ). The WCQ is a patient self-report instrument to document side-effects of chemotherapy. Literature review of relevant studies shows that psychometric testing of similar instruments is rarely rigorous. Content validity for the WCQ was established in five ways: literature review, Delphi review among oncology staff, pre-pilot unstructured interviews, pilot study and amendment of the instrument and items for spontaneous reporting of problems on the questionnaire. A three-stage approach to construct validity was used. The hypothesis adopted was that as certain cytotoxic agents cause stomatitis, incidence and severity of stomatitis will decrease following cessation of treatment. Stage 1: factor analysis confirmed the presence of a sole factor, with an eigenvalue of 5.3, for mouth problems which explained 65.5% of the variance. Stage 2: the hypothesis was confirmed using research findings. Stage 3: the Wilcoxon test showed highly significant results for during and post chemotherapy stomatitis scores. Reliability of the questionnaire was assessed using the test-retest method. Weighted kappa was chosen as the test statistic. A median value of wk = 0.87 was obtained. The results indicate that the WCQ is a reliable and valid instrument.

This paper reports findings from the pilot stage of a longitudinal descriptive study of problems experienced by day-patients undergoing chemotherapy treatment with the Day Ward, Worthing Hospital. Unlike the majority of studies in this field, this study allows documentation of all side-effects perceived by the patient as important, and is designed to follow the progress in incidence and severity of each problem through the treatment course. Preliminary findings show some 100 side-effects have been identified, with different problems being most troublesome for each treatment regime. Full data are provided. The study emphasises the importance of regime-specific data both in formulating clinical practice and in the provision of patient education.

The management of symptoms experienced by patients receiving cytotoxic chemotherapy influences quality of life during treatment. Symptom management may be improved through a structured approach to symptom assessment. This paper describes the development of the Chemotherapy Symptom Assessment Scale (C-SAS), a 24-item scale designed for the routine assessment of symptoms experienced by patients receiving cytotoxic chemotherapy. The scale development process focused both upon the psychometric properties and the clinical usefulness of the scale. Patients and health professionals played a significant role in item selection and scale design in order to maximise the clinical utility of the C-SAS.