Fragment optimization and elaboration strategies – the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits
Christopher R. Smith, Svitlana Kulyk, Misbha Ud Din Ahmad, Valentina Arkhipova, James G. Christensen, Robin J. Gunn, Anthony Ivetac, John M. Ketcham, Jon Kuehler, J. David Lawson, Nicole C. Thomas, Xiaolun Wang, Matthew A. Marx
Abstract
-deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719.
Topics & Concepts
Fragment (logic)Drug discoveryComputational biologyElaborationLead compoundCombinatorial chemistryChemistryStereochemistryBiologyComputer scienceBioinformaticsBiochemistryAlgorithmIn vitroArtHumanitiesCancer-related gene regulationSynthesis and Catalytic ReactionsChemical Synthesis and Analysis