Prof Paul Workman; Centre for Cancer Drug Discovery, The ¹û½´ÊÓƵ of Cancer Research
Paul Workman is a leading cancer research scientist known for pioneering many innovative cancer drugs and personalised medicines targeted at specific molecular abnormalities, a strategy he terms ‘drugging the cancer genome’. He also introduced the ‘Pharmacological Audit Trail’ – a concept and practical framework that is now widely-used, employing biomarkers to support informed drug development decisions. Paul’s multidisciplinary drug discovery research has closely integrated chemical biology approaches, and his teams have discovered multiple clinical drug candidates and chemical probes for protein and lipid kinases and molecular chaperones like HSP90. Of note he was instrumental in the discovery of the approved EGFR inhibitor gefitinib (for EGFR mutant non-small cell lung cancer) and the approved AKT inhibitor capivasertib (for ER-positive breast cancer). With experience in academia, biotech and pharma, Paul has pioneered the non-profit, academic team science model for drug discovery. Notably, he built and directed the CRUK Cancer Therapeutics Unit at The ¹û½´ÊÓƵ of Cancer Research (ICR) in London from 1997 to 2016, where he was pivotal in the discovery of 21drug candidates, 13 of which entered clinical trials. From 2014-21, Paul also served as Chief Executive and President of ICR. In addition, Paul was a Co-Founder of the biotech companies Chroma Therapeutics and Piramed Pharma, and is a Science Partner at Nextech Invest. He has won numerous awards and fellowships. Paul is a Fellow of the Royal Society (the UK’s national academy of science),Fellow of the Academy of Medical Sciences (the UK’s national academy of medicine) and Fellow the Royal Society of Chemistry, and he is also a Fellow of the American Association for the Advancement of Science. Last year, Paul was named as the 2024 International Chemical Biology Society Global Lectureship Awardee and this year he was elected as a Fellow of the prestigious AACR Academy, Class of 2025, to which he will be inducted at the annual AACR meeting in Chicago. Paul obtained his PhD in Cancer Pharmacology at Leeds University, and before joining ICR he held senior leadership roles at AstraZeneca, the CRUK Beatson Laboratories at Glasgow University and the MRC Clinical Oncology Unit at Cambridge University. He also spent an UICC ICRETT Fellowship-funded sabbatical at Stanford University. Paul is currently Harrap Professor of Pharmacology and Therapeutics at the ICR, Co-Director of the CRUK Children’s Brain Tumour Centre of Excellence, hosted at ICR and Cambridge University, and Executive Director of the non-profit Chemical Probes Portal – an open science resource, hosted at ICR, to improve the selection and use of chemical tools in biomedical research.
There is considerable interest in stress response pathways as potential therapeutic vulnerabilities in cancer and other diseases. Tumour cells require these pathways to deal with stresses such as oncogene overdrive and adverse microenvironmental conditions. NXP800was discovered in Workman’s team at the ICR and licenced to the biotech company Nuvectis Pharma for clinical development. The drug was optimised by medicinal chemistry from a hit compound that Paul’s team discovered in a cell-based phenotypic pathway screen for inhibitors of the Heat Shock Factor 1 (HSF1) transcription factor-mediated stress pathway. The talk will describe the 15-year rollercoaster journey to discover NXP800 and the use of chemical biology approaches to progressively elucidate its complex molecular mechanism of action, including an essential requirement for the activation of the EIF2alpha kinase GCN2 and the Integrated Stress Response, leading in turn to suppression of the HSF1 transcriptional activity. Paul will also describe his team’s discovery of the highly selective effects of NXP800 in models of ARID1A mutant ovarian cancer and efforts to elucidate the mechanism underlying this biomarker, which is being used for patient selection. Finally, Paul will show data from the early Phase 1a clinical trial of NXP800 and the use of the Pharmacological Audit Trail approach (which he conceived and exemplified) to evaluate the drug in ARID1A mutant ovarian cancer patients (NCT05226507, collaboration with the GOG and ENGOT cooperative groups). NXP800 has received both FDA FastTrack and Orphan Drug Designations for the treatment of high unmet need platinum-resistant, ARID1A-mutated ovarian carcinoma and is also undergoing Phase 1b evaluation in patients with advanced or metastatic cholangiocarcinoma (bile duct cancer, NCT06420349)for which FDA has also granted Orphan Drug status.
Networking tea, coffee and cake will follow the talk.
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