molecules of the year

The ARIAD/Takeda EGFR exon 20 insertion mutant (EGFRex20ins) inhibitor TAK-788 is a Breakthrough Therapy for patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 20 insertion mutations.  The appearance of exon 20 insertions is a common resistance mechanism to earlier generations of EGFR inhibitors including osimertinib, to which TAK-788 is structurally related. 1st and 2nd generation EGFR inhibitors partly depend on the fact that mutant forms of EGFR have destabilized inactive forms with reduced ATP affinity relative to wild-type (WT) EGFR, making the mutant forms easier to drug in cells. EGFR exon 20 mutants, however, have active sites that are very similar to WT, making tumors bearing these mutations difficult to drug without significant side effects due to WT inhibition. This oral…