Identification of M4205A Highly Selective Inhibitor of KIT Mutations for Treatment of Unresectable Metastatic or Recurrent Gastrointestinal Stromal Tumors

The treatment of gastrointestinal stromal tumors (GISTs)
driven
by activating mutations in the KIT gene is a prime
example of targeted therapy for treatment of cancer. The approval
of the tyrosine kinase inhibitor imatinib has significantly improved
patient survival, but emerging resistance under treatment and relapse
is observed. Several additional KIT inhibitors have been approved;
still, there is a high unmet need for KIT inhibitors with high selectivity
and broad coverage of all clinically relevant KIT mutants. An imidazopyridine
hit featuring excellent kinase selectivity was identified in a high-throughput
screen (HTS) and optimized to the clinical candidate M4205 (IDRX-42).
This molecule has a superior profile compared to approved drugs, suggesting
a best-in-class potential for recurrent and metastatic GISTs driven
by KIT mutations.