Avapritinib (BLU-285) is a selective, highly potent, and orally active inhibitor of KIT and PDGFRA activation loop mutant kinases, targeting KIT D816V (IC50:0.27 nM) and PDGFRA D842V (IC50:0.24 nM), and attenuates the transport functions of ABCB1 and ABCG2. It binds to the active conformation of the kinases and exhibits antitumor activity.

ABCB1:5 μM (EC50, ATPase activity), KIT D816 (human HMC1.2 cells):4 nM, KIT D816 (mouse P815):22 nM, c-Kit (D816V):0.27 nM, ABCG2:0.2 μM (EC50, ATPase activity), PDGFRα (D842V):0.24 nM

Avapritinib (BLU-285) has demonstrated biochemical in vitro activity against the KIT exon 17 mutant enzyme, KIT D816V, with an IC50 value of 0.27 nM; the cellular activity of BLU-285 on the KIT D816 mutant was measured by autophosphorylation in the human mast cell leukemia cell line HMC1.2 and the P815 mouse mastocytoma cell line, with IC50 values ​​of 4 and 22 nM, respectively. [1]

METHODS: After a 21-day latency period post-injection, mice were orally administered Avapritinib (BLU-285) once daily at a dose of 10 mg/kg or 30 mg/kg until day 45. The efficacy of Avapritinib (BLU-285) in KIT exon 17 mutant CBF-AML was evaluated using the Kasumi-1 luc+ AML NOG SCID mouse femoral injection model.
RESULTS Both doses (10 or 30 mg/kg, oral, once daily) of Avapritinib (BLU-285) significantly reduced disease burden throughout the study. Avapritinib (BLU-285) at 10 or 30 mg/kg resulted in tumor regression in all animals. [1]

A Kasumi-1 luc+ AML NOG SCID mouse femoral injection model is used to assess the efficacy of Avapritinib (BLU-285) in KIT exon 17-mutated CBF-AML. Following a 21 day post-injection latency period, mice are dosed with Avapritinib orally, once daily at 10 mg/kg or 30 mg/kg through day 45. Control groups are treated with vehicle or Cytarabine administered 100 mg/kg i.p once weekly.