molecules of the month

Overcoming FGFR mutation resistance and FGFR1-mediated hyperphosphatemia toxicity through isoform-selective FGFR2/3 inhibition. “Compound 29” is an ATP-competitive fibroblast growth factor receptor (FGFR) 2/3 inhibitor with subnanomolar potency. FGFR is a receptor tyrosine kinase (RTK) involved in cell differentiation, proliferation, migration and survival. Aberrations in the FGFR1-4 gene are related to oncogenesis and found in 5-10% of all human cancers, with a higher incidence of 10-30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. FGFR1-3 inhibitors erdafitinib (Balversa), pemigatinib (Pemazyre), and infigratinib (Truseltiq) were FDA-approved in 2019-21, but clinical resistance has been reported due to gatekeeper (GK) mutations FGFR2V564I/L/M/F or FGFR3V555I/L/M/F such that the 3,5-dimethoxyphenyl group can no longer reside in the hydrophobic pocket of the ATP-binding site. Even further, it has been…