The fibroblast growth factor receptor (FGFR) family of tyrosine kinases consists of four isoforms (numbered 1-4), which are structurally similar to each other but play very different roles in human cancer.
Fusions, point mutations and gene amplifications in individual isoforms of the FGFR family have been associated with distinct cancer types in patients. While tyrosine kinase inhibitors (TKIs) with anti-FGFR activity have produced clinical responses in patients whose tumors harbor FGFR alterations, currently available FGFR TKIs inhibit multiple other kinases, including multiple isoforms of FGFR. As a result, dose-limiting toxicities have been observed frequently in patients. Specifically, we believe that sparing FGFR1 may be an important attribute for maximizing therapeutic inhibition of FGFR2 and FGFR3 in patients whose tumors harbor genetic abnormalities in those two genes.
In vitro and in vivo data presented at the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics demonstrate the chemistry estate we have built thus far, and the potential for an FGFR1-sparing molecule to maximize therapeutic index. Read the poster presented at AACR-NCI-EORTC here.