XPose Therapeutics

I am delighted to share that Prof. Kevan Shokat and my book has now been published - “RAS Drug Discovery: Past, Present and Future” – a comprehensive technical overview of many of the drug discovery approaches in the public domain being deployed to target RAS. It is now available as both an E-book, and hardcopy: https://lnkd.in/dxMNuQDm RAS Drug Discovery: Past, Present and Future is a comprehensive overview of the historical and current state-of-the-art drug discovery approaches toward targeting the formerly undruggable oncogene, RAS. It includes seminal medicinal chemistry case histories of KRASG12C inhibitors such as LUMAKRAS® (sotorasib), the ­first approved KRASG12C inhibitor for NSCLC, alongside the latest advances toward identi­fication of in vivo tools and development candidates targeting both mutant-speci­fic RAS isoforms such as KRASG12D, alongside RAS-multi and pan-KRAS inhibition approaches. This book also provides the reader with a comprehensive overview of the in vitro assay systems, in vivo pharmacology xenograft models, and chemical biology tools available to characterize small molecule inhibitors of RAS. It has been a pleasure working with my co-editor Prof. Kevan Shokat on this project, and we are grateful to all the chapter authors for their excellent contributions (see outline below). We would also like to thank the team at Elsevier – especially Dan Egan and Paul Chandramohan for their support. We hope this book will be a useful resource for all the RAS drug hunters out there and for anyone who is interested in learning more about this field. #RAS, #Outsmartcancer, #MedicinalChemistry, #DrugDiscovery https://lnkd.in/dxMNuQDm

3 key features of the exciting news on Merck’s $30M acquisition of Modifi Biosciences: preclinical asset, novel DDR (DNA Damage Response) target, and GBM (glioblastoma), items that would make investors want to stay away as the article describes. Provides encouragement and potential trajectory for other companies working on novel DDR targets for GBM in early/preclinical drug discovery (XPose Therapeutics). #oncology #therapeutics #drugdiscovery https://lnkd.in/dJUZA_cN

Back in San Diego in a couple of days for the “Precision in Drug Discovery & Preclinical Summit San Diego” 2024. Looking forward to presenting our talk on “Discovery and development of novel DNA repair inhibitors as precision oncology therapeutics” (on behalf of XPose Therapeutics) and being a panelist on “Balancing The Human Expertise and Artificial Intelligence in Drug Development”. #drugdiscovery #therapeutics #oncology #PDDPSUMMIT Precision Evolution Global

NP-association anecdote today as the world felicitates today’s 2024 Nobel Prize in Chemistry to David Baker, John Jumper and Briton Demis Hassabis, for protein structure design, modeling and prediction, a few reminders of the underlying experimental data of protein experimental structures determined by protein X-ray crystallography and deposited by scientists around the world over a few decades into the Protein Data Bank (PDB), plus the hundreds of crystal structures we have determined in the past 10 years at Accelero Biostructures that enabled and continues to enable experimental biology, drug discovery and computational modeling. Some key milestones and references: 1) Sung-Hou Kim’s (Berkeley, Plexxikon Co-Founder, my postdoc advisor, advisor to the prolific academic/entrepreneur George Church and a long line of others) seminal paper on “Structure-based assignment of the biochemical function of a hypothetical protein: A test case of structural genomics” that kicked off the structural genomics/Protein Structure Initiative (for example, at Berkeley Structural Genomics Center led by Sung-Hou Kim, and at Joint Center for Structural Genomics led by Ian Wilson) leading to massive gains in development of HT crystallography (synchrotron-based) and deposition of thousands of novel protein X-ray/crystal structures into the PDB, which provided training data, https://lnkd.in/gaMt4Ueg 2) Protein Data Bank (PDB) for collating and curating all the protein structure data, which aside from massive advances in structural biology/biology, have also been involved in over 200 FDA-approved drugs, https://lnkd.in/gqsNTDiA 3) My personal joy and gratitude today at having a 3rd co-authored paper with a Nobel Laureate, David Baker, from 2011, https://lnkd.in/gi7NRVMT (original reference https://lnkd.in/g5DBVv5z), with the other 2 papers being with 2012 Physiology or Medicine Nobel Laureate Shinya Yamanaka (https://lnkd.in/gVK24j3j), and the 2013 Chemistry Nobel Laureate Michael Levitt (https://lnkd.in/gb6vtvGe). #structuralbiology #drugdiscovery #therapeutics

Great to see the 2024 Nobel Prize in Physiology and Medicine awarded to Victor Ambros and Gary Ruvkun for pioneering work on microRNA, including a Berkeley connection (Gary Ruvkun was born in Berkeley). Coincidentally, quite a lot of interest also in the overlap of DDR (DNA Damage Response) and miRNA in oncology, including this new review on potential synergies of our target APE1 and miRNA (“DNA-repair enzyme APE1 is part of the EV protein cargo with a novel post-transcriptional role for this ubiquitous DNA-repair enzyme that could explain its role in cancer progression.”) https://lnkd.in/gaGPRjJN https://lnkd.in/g39snsri #therapeutics #drugdiscovery #oncology

After a slew of 2024 publications on WRN helicase noncovalent and covalent inhibitors in MSI-cancers/DDR (Novartis, GSK, Vividion, H3 Biomedicine), including structure-based drug discovery/protein X-ray crystallography, new results on a backup TPD/PROTAC/degrader approach (MRC) for WRN helicase. #oncology #therapeutics #drugdiscovery

FDA-approved cancer drugs target < 200 proteins. For those working on new targets (scientific validation but without clinical validation, a chicken-and-egg problem given that’s it’s hard if not impossible to have clinical validation without some early/preclinical investment in hit finding and lead development), in this new publication in Cell, the authors integrated CPTAC (Clinical Proteomics Tumor Analysis Consortium) proteogenomics data from 1043 patients across 10 cancers with other public datasets (pan-cancer analysis, proteomic data from tumors and genetic screens from cell lines, synthetic lethality) including breast invasive carcinoma (BRCA), clear cell renal cell carcinoma (CCRCC), colon adenocarcinoma (COAD), glioblastoma (GBM), head and neck squamous cell carcinoma (HNSCC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LSCC), ovarian serous cystadenocarcinoma (OV), pancreatic ductal adenocarcinoma (PDAC), and uterine corpus endometrial carcinoma (UCEC). Results categorize large number of potential therapeutic targets. Hope this will encourage scientists and investors working on novel targets. #drugdiscovery #therapeutics https://lnkd.in/gfBkKg7k