ErbB2 is a receptor tyrosine kinase that belongs to a family of four receptors EGFR, ErbB2, ErbB3, and ErbB4, also known as HER1, 2, 3, 4. ErbB2 amplifications and mutations occur in a mutually exclusive fashion (80-90% of cases) and represent independent drivers of human cancer pathogenesis. Activating mutations in the ErbB2 gene have been identified in multiple cancers and demonstrate a tumorigenic role similar to that of ErbB2 amplification.
The non-selective dual EGFR/ErbB2 inhibitors are active against ErbB2 point mutations, however, inhibition of EGFR leads to dose limiting toxicities that include severe rash, diarrhea and mucositis. Tucatinib, the first-generation selective EGFR sparing ErbB2 inhibitor, does not reach clinical plasma concentrations to cover the IC90 efficacious concentration for prevalent ErbB2 mutations.
CGT1786 is a covalent ErbB2 inhibitor with enhanced ErbB2 /EGFR kinetic selectivity compared with the approved inhibitors neratinib and afatinib, showing over 50-fold selectivity against EGFR but similar efficacious rates of ErbB2 inactivation. CGT1786 Demonstrates robust inhibition of tumor phospho ErbB2 levels in a 3T3 L755S breast cancer model and shows superior tumor growth inhibition compared to tucatinib in a 3T3 L755S model…
