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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 in Computational Chemistry
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.
Bio
Brandi Hudson is a Principal Scientist in Computational Chemistry, utilizing in silico modeling and structure-based drug design to discover therapies for cancer and rare diseases. She spent two years at Remix Therapeutics, applying a model-first approach to hit validation, fragment X-ray screening, and lead optimization across multiple RNA-targeting programs. Before that, she spent five years at Relay Therapeutics, where she was part of the team that discovered lirafugratinib (RLY-4008), a highly selective FGFR2 inhibitor. Lirafugratinib is currently in the global ReFocus trial for FGFR2-altered tumors and has received FDA breakthrough therapy and orphan drug designations. Beyond her scientific contributions, Brandi is passionate about diversity, equity, and inclusion. In January 2020, she launched Relay’s Diversity, Equity, Belonging, & Inclusion (DEBI) initiatives, leading efforts for over three years. During this time, she oversaw the creation of two employee resource groups, introduced company-wide DEI training, implemented inclusive meeting practices, and organized year-round events celebrating diversity. In recognition of her impacts at Relay, she was named to Google Ventures’ Impact List in 2021. Brandi completed her postdoctoral training in structural biology at UCSF (2018), earned a Ph.D. in Chemistry from UC Davis (2016), and received a B.S. in Chemistry from the College of Charleston (2011). Between college and graduate school, she worked as a chemist at o2si, a chemical standards company, and spent a year as an adjunct organic chemistry lab instructor at Trident Technical College.