EGFR/HER2 mutant-selective inhibitor BH-30643

An orally bioavailable, mutant-selective, reversible macrocyclic inhibitor of human epidermal growth factor receptor (EGFR) and epidermal growth factor receptor 2 (HER2), with potential antineoplastic activity. Upon oral administration, EGFR/HER2 mutant-selective inhibitor BH-30643 targets, reversibly binds to, and inhibits the activity of EGFR with selective mutations, including, but not limited to, classical mutations, exon 20 insertion (Ex20ins) activating mutations as well as various resistance mutations, such as ex19del/T790M, ex19del/C797S, ex19del/T790M/C797S, L858R/T790M, L858R/C797S, and L858R/T790M/C797S. In addition, BH-30643 reversibly binds to and inhibits HER2 mutations, including ex20ins mutations. This prevents EGFR- and HER2-mediated signaling and may result in the inhibition of tumor growth in certain mutant EGFR/HER2-expressing tumors. EGFR and HER2, receptor tyrosine kinases mutated or overexpressed in many tumor cell types, play major roles in tumor cell proliferation and tumor vascularization. By largely sparing wild-type (WT) EGFR, BH-30643 may decrease the risk of EGFR-related toxicities. Since BH-30643 concurrently targets activating mutations in EGFR and HER2, it reduces the chances of resistance.