Oncogenic mutations affecting FGFR2 and FGFR3 (including short variant point mutations and fusions) are expressed across a range of cancers such as bladder and cholangiocarcinoma. While these mutations have been targeted by first generation pan-FGFR inhibitors (erdafitinib, pemigatinib and infigratinib), clinical success has been hindered by dose limiting toxicities related to on-target inhibition of FGFR1. Inhibition of FGFR1 has been known to cause hyperphosphatemia, in turn leading to significant dose interruptions, reductions, and discontinuations that can limit the effectiveness to treat cancers driven by FGFR2/3 mutations. Furthermore, current FGFR inhibitors are limited by acquired resistance due to mutation of gatekeeper positions in FGFR2/3, which are residues that modulate access to the ATP-binding site. Next generation FGFR2/3 inhibitors that potently target primary and resistance mutations while sparing FGFR1 are critically needed.

Our FGFR program leverages our MAP discovery engine to (i) define the full spectrum of FGFR2/3 oncogenic mutations,; (ii) classify mutations according to unifying conformational changes; and (iii) design small molecule inhibitors that are active against the full spectrum of oncogenic FGFR2/3 mutations, exhibit activity against clinically relevant resistance mutations, and achieve selectivity versus FGFR1. We believe that our MAP discovery engine is differentiated by its capability to identify development candidates that are selective versus FGFR1.

BDTX FGFR program compounds are MasterKey inhibitors of allosteric FGFR2/3 mutations with selectivity versus FGFR1 and activity against clinically relevant resistance mutations.