A small molecule inhibitor OGP46 is effective against imatinib-resistant BCR-ABL mutations including T315I through BCR-ABL/JAK-STAT pathway
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 the 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 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 inducing by cell differentiation through 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 that are resistant to imatinib. Thus, OGP46 maybe a novel strategy for overcoming imatinib-resistance BCR-ABL mutations including T315I.
Publisher URL: https://www.sciencedirect.com/science/article/pii/S2372770520300875
DOI: 10.1016/j.omto.2020.06.008
Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.
Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.