Design and Synthesis of BLU-654, a Potent and Selective Mutant KIT V654A Inhibitor for the Treatment of Imatinib-Resistant GIST.

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma of the gastrointestinal tract, with approximately 5000 new cases annually in the USA. Approximately 80% of GIST cases are driven by activating mutations in KIT in exon 9 or 11. Resistance to present therapies like imatinib often arises from secondary KIT mutations, especially V654A (exon 13), which is the most frequent resistance mutation. Tyrosine kinase inhibitors (TKIs) currently approved for GIST can cause dose-limiting side effects due to off-target inhibition of other kinases. Herein, we report the discovery and optimization of BLU-654 (compound 18), a highly potent and kinome-sparing KIT V654A inhibitor. Preclinical efficacy studies demonstrated its prolonged antitumor activity in a KIT V654A cell-derived xenograft mouse model. BLU-654 offers a potent and selective profile suitable for combination therapy for KIT-mutant GIST patients.