molecules of the month

The First Isoform-Selective FGFR2 Inhibitor The FGFR family of receptors are well-validated targets in cancer, and several pan-FGFR inhibitors that have strong activity against FGFR1-4 have reached approval including pemigatinib, infigratinib, futibatinib, and erdafitinib. While specific FGFRs like FGFR2 can drive cancers like cholangiocarcinoma, broad inhibition of FGFRs leads to significant off-target toxicities, such as hyperphosphatemia from FGFR1 inhibition or diarrhea from FGFR4 inhibition. Due to the 88-96% sequence similarity of the FGFR2 and FGFR1/3/4 kinase domains, however, an FGFR2-specific inhibitor has until recently been elusive. Relay Therapeutics captured industry attention when they announced their discovery of an FGFR2 isoform-selective inhibitor using an approach involving molecular dynamics simulations (“Dynamo” platform), leading many to wonder how they were able to accomplish…