Dr. Albert Antolin obtained a PhD in Pharmacoinformatics (Pompeu Fabra University,Spain) pioneering the application of polypharmacology prediction to chemical biology by uncovering off-targets of chemical probes. Dr. Antolin was subsequently awarded a Marie Curie Fellowship to join the Institute of Cancer Research (UK) to develop the first objective resource for the assessment of chemical probes (https://probeminer.icr.ac.uk/). Next, Dr. Antolin won a Wellcome Fellowship to explore the polypharmacology of cancer drugs and their implications for precision oncology. Having worked in industry and academia, Dr. Antolin is interested in bridging industrial drug discovery with remaining fundamental questions in cancer chemical systems biology
From probe to drug: Polypharmacology across drug discovery
Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we present the use of computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 and PARP inhibitors. We demonstrate that the HSP90 inhibitors ganetespib and luminespib and the PARP inhibitors rucaparib and niraparib display unique off-target kinase pharmacology as compared to other clinical inhibitors of the same class, with important implications for personalized prescription. We also demonstrate that the early PARP chemical tool PJ34 displays a different polypharmacology than several FDA-approved PARP inhibitors, with important implications for target validation and the practise of chemical biology. We finally demonstrate that polypharmacology evolved during the optimisation to discover luminespib and that the hit, leads and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities as well as identifying undesired toxicity and unexplained cellular effects.
Back to speaker overview Back to Oral- and Flash presentations overview