Abstract
The small-molecule inhibitor BLU-285 inhibits clinically relevant KIT and PDGFRA mutations.
Major finding: The small-molecule inhibitor BLU-285 inhibits clinically relevant KIT and PDGFRA mutations.
Approach: Small-molecule kinase inhibitors were designed to inhibit a panel of primary and resistance KIT mutations.
Impact: BLU-285 may be a potential therapeutic option for patients with diseases harboring KIT/PDGFRA mutations.
Patients with gastrointestinal stromal tumors (GIST) harboring activating KIT mutations initially respond to imatinib treatment, but most patients acquire a secondary KIT mutation that decreases imatinib binding affinity and results in relapse. To further elucidate the mechanisms underlying the function of KIT/PDGFRA mutations, Evans and colleagues characterized the binding of primary or resistance mutations by type I and II kinase inhibitors, which bind to the activation loop or the inactive conformation of mutant kinases, respectively. Type I inhibitors bound to both activation loop and inactive conformation KIT mutants, whereas type II inhibitors primarily bound to inactive conformation KIT mutants. Rational design based on the most promising core chemical structures and pharmacokinetic optimization resulted in the development of the small-molecule KIT inhibitor BLU-285, which exhibited a kinome profile similar to that of imatinib and was more selective than several other type I inhibitors. Further, BLU-285 was more efficacious than type I (dasatinib) and II (imatinib, sunitinib, regorafenib) inhibitors against clinically relevant primary and resistance KIT/PDGFRA mutations in vitro and in vivo, respectively. In a first-in-human Phase I trial, treatment with BLU-285 resulted in the reduction of tumor size and PDGFRA mutant–positive circulating tumor DNA (ctDNA) in a patient with PDGFRA mutant GIST and tumor reduction in a patient with GIST harboring a secondary KIT activation loop mutation. Similarly, a patient with systemic mastocytosis, which is characterized by the accumulation of excess mast cells and frequently harbors a KIT activation loop mutation, exhibited decreased levels of bone marrow mast cells after treatment with BLU-285. Together, these results describe the design and activity of the type I KIT/PDGFRA inhibitor BLU-285 and suggest that BLU-285 may be a potent therapy against diseases harboring clinically relevant KIT and PDGFRA mutations.
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