The discovery of new inhibitors of KIT for the treatment of GIST
Dr. Andreas Blum
Merck Healthcare KGaA
Merck Healthcare KGaA
The treatment of gastrointestinal stromal tumors (GIST) 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 mutations in KIT 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. Based on KIT inhibitor scaffolds identified within the Merck compound collection, a 3,5,6-substituted indazole-lead was discovered. Substituent optimization in the 5- and 6-positions of the core scaffold resulted in highly selective KIT kinase inhibitors. Through variation at the 3-position, potency and physicochemical properties were optimized, resulting in the candidate molecule M4645 which combined potency, kinase selectivity, and solubility with a good safety profile. In parallel, an imidazopyridine hit featuring excellent kinase selectivity and ADME-properties was identified in a high-throughput screen (HTS). The optimization was supported by elucidation of the binding mode of the series, determined by X-ray crystallography. The 6-position provided an exit-vector to modulate the ADME-properties of the molecules and an ether linkage proved to be optimal for potency. The SAR in the 3-position was very steep and a 4,6-substituted pyrimidine was identified as optimum for potency and metabolic stability. The benzylic substituent is deeply buried and is crucial for high on target potency. As metabolic weak spot in the hit structure, this residue needed careful optimization. During the optimization, the selectivity against the kinome and the activity against KIT mutants was constantly monitored to maintain the high selectivity of the initial hit and to achieve broad coverage of oncogenic and resistance mutations of KIT leading 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 GIST driven by KIT mutations. M4205 (IDRX-42) is currently being studied in a phase 1 first-in-human study in participants with advanced GIST.