Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm primarily due to the presence of the Bcr-Abl fusion gene that produces the constitutively active protein, Bcr-Abl. Imatinib, a BCR-ABL-targeted drug, is a first-line drug for the treatment of CML. Resistance to imatinib occurs as a result of mutations in the Bcr-Abl kinase domains. In this study, we evaluated S116836, a novel Bcr-Abl Inhibitor, for its anti-cancer efficacy in the wild-type (WT) and T315I mutant Bcr-Abl. S116836 was efficacious in BaF3 cells with WT or T315I mutated Bcr-Abl genotypes. S116836 inhibits the phosphorylation of Bcr-Abl and its downstream signaling in BaF3/WT and BaF3/T315I cells. Mechanistically, S116836 arrests the cells in the G0/G1 phase of cell cycle, induces Apoptosis, increases ROS production, and decreases GSH production in BaF3/WT and BaF3/T315I cells. Moreover, in mouse tumor xenografts, S116836 significantly inhibits the growth and volume of tumors expressing the WT or T315I mutant Bcr-Abl without causing significant cardiotoxicity. Overall, our results indicate that S116836 significantly inhibits the imatinib-resistant T315I Bcr-Abl mutation and could be a novel drug candidate for treating imatinib-resistant CML patients.