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.

由KIT基因（KIT gene）激活突变驱动的胃肠道间质瘤（gastrointestinal stromal tumors, GISTs）的治疗，是癌症靶向治疗的经典范例。酪氨酸激酶抑制剂伊马替尼的获批显著改善了患者的生存预后，但治疗过程中出现的获得性耐药与复发仍时有发生。目前已有多款额外的KIT抑制剂获批上市，但临床上仍存在高度未被满足的医疗需求：亟需兼具高选择性且能覆盖所有临床相关KIT突变体的KIT抑制剂。研究人员通过高通量筛选（high-throughput screen, HTS）发现了一款兼具优异激酶选择性的咪唑并吡啶类命中化合物，并将其优化为临床候选化合物M4205（IDRX-42）。该分子相较于已获批药物具备更优异的特性，展现出针对KIT突变驱动的复发及转移性胃肠道间质瘤的同类最优开发潜力。