Wednesday, March 19, 2025
4 to 5 p.m.
Chemistry Annex 1024
Reception to follow in CLSL A Atrium
Speaker: Dr. Brandi Hudson
Principal Scientist
Remix Therapeutics
Lecture: "Leveraging Differences in Drug Discovery: Computer-aided drug design of Lirafugratnib, a highly selective, covalent small molecule inhibitor of FGFR2"
Abstract
Inhibitors of fibroblast growth factor receptor 2 (FGFR2) kinase have shown promise in treating intrahepatic cholangiocarcinoma and other advanced solid tumors, but their toxicity often leads to dose reductions or interruptions, limiting efficacy. The most common adverse effect, hyperphosphatemia, arises from FGFR1 inhibition due to the lack of isoform selectivity. Using computational chemistry techniques, including molecular dynamics simulations, we identified and leveraged differences in P-loop motion between FGFR1 and FGFR2 to design a selective, covalent FGFR2 inhibitor. This effort led to the development of lirafugratinib, which demonstrates ~250-fold selectivity over FGFR1 in vitro, causes tumor regression in FGFR2-altered xenograft models, and achieves clinical efficacy without inducing significant hyperphosphatemia. Fostering innovation, collaboration, and psychological safety empowers teams to tackle complex challenges we encounter in drug discovery. I’ll share my journey and key principles that transformed team dynamics and promoted an inclusive environment.