Aberrant signaling of the FGF/FGFR pathway occurs in 7% of cancers and is an oncogenic driver in many solid tumors including bladder, breast, endometrial, gastric, hepatocellular, lung, and ovarian cancers. There is a compelling medical need for a highly selective inhibitor of all four FGFR family members, FGFR1-4, to improve clinical responses in patients while minimizing off-target toxicity. Principia Biopharma, a pioneer in covalent drug discovery and development, has addressed this need with the discovery of PRN1371, an oral, low dose, highly selective, covalent irreversible inhibitor of fibroblast growth factor receptor (FGFR) 1-4.<br/><br/>The discovery and development of covalent drugs presents unique challenges. Starting from a 7-oxopyridopyrimidine core, we applied structure-based design to incorporate a Michael acceptor appropriately positioned to engage Cys 488 in a covalent bond. To guide lead optimization, specialized assays were developed to measure FGFR target occupancy and assess the ADME liabilities of Michael acceptors. The final selection of PRN1371 as a clinical candidate was based upon the ideal combination of selectivity, potent and prolonged pharmacodynamic inhibition of FGFR1-4 in vivo and high predicted human oral absorption. PRN1371 is now being investigated in a Phase 1/2 open-label, multicenter clinical trial for solid tumors.

Discovery of PRN1371: A highly selective, irreversible inhibitor of FGFR1-4 in clinical development for the treatment of solid tumors

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.