A Small Molecule Inhibitor, OGP46, Is Effective against Imatinib-Resistant BCR-ABL Mutations via the BCR-ABL/JAK-STAT Pathway

• Published in: Molecular therapy. Oncolytics 2020-09, Vol.18, p.137-148
• Main Authors: Wei, Liuya, Yang, Yang, Gupta, Pranav, Wang, Aihong, Zhao, Min, Zhao, Yao, Qu, Mei, Ke, Yu, Liu, Ying, Liu, Hong-Min, Xu, Xin, Sun, Yanli, Chen, Zhe-Sheng, Hu, Zhenbo
• Format: Article
• Language: English
• Subjects: BCR-ABL kinase; BCR-ABL mutations; cell differentiation; chronic myeloid leukemia; imatinib resistance; JAK-STAT pathway; T315I mutation; targeted therapies
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2020.06.008

Chronic myeloid leukemia (CML) is caused by the Philadelphia (Ph+) chromosome carrying the BCR-ABL oncogene, a constitutively active tyrosine kinase. The discovery of imatinib represents a major success story in the treatment against CML. However, mutations in the BCR-ABL kinase domain are a major cause of resistance to imatinib, demonstrating that BCR-ABL remains a critical drug target. Here, we investigate a novel small molecule inhibitor, OGP46, for its inhibitory activity against K562, a panel of murine BaF3 cell lines stably expressing either wild-type BCR-ABL or its mutant forms, including T315I. OGP46 exhibits potent activity against imatinib-resistant BCR-ABL mutations, including T315I. OGP46 induced cell differentiation accompanied by G0/G1 cell-cycle arrest and suppressed the colony formation capacity of cells. Treatment with OGP46 significantly decreased the mRNA and protein expression of BCR-ABL in K562 and BaF3-p210-T315I cells. Mechanistically, the anti-cancer activity of OGP46 induced by cell differentiation is likely through the BCR-ABL/JAK-STAT pathway in native BCR-ABL and mutant BCR-ABL, including T315I, of CML cells. Our findings highlight that OGP46 is active against not only native BCR-ABL but also 11 clinically relevant BCR-ABL mutations, including T315I mutation, which are resistant to imatinib. Thus, OGP46 may be a novel strategy for overcoming imatinib-resistance BCR-ABL mutations, including T315I. [Display omitted] Chen and colleagues demonstrate that a small molecule, OGP46, is active against not only native BCR-ABL but also 11 clinically relevant BCR-ABL mutations, including T315I, that are resistant to imatinib by cell differentiation through the BCR-ABL/JAK-STAT pathway, which provides a novel strategy for overcoming imatinib-resistance BCR-ABL mutations in chronic myeloid leukemia.