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
Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang 261042, China.
School of Pharmacy, Weifang Medical University, Weifang 261053, China.
Mol Ther Oncolytics. 2020 Jun 9;18:137-148. doi: 10.1016/j.omto.2020.06.008. eCollection 2020 Sep 25.
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.
慢性髓性白血病（CML）由携带BCR-ABL致癌基因的费城（Ph）染色体引起，该基因是一种组成型活性酪氨酸激酶。伊马替尼的发现是治疗CML的一个重大成功案例。然而，BCR-ABL激酶结构域的突变是对伊马替尼耐药的主要原因，这表明BCR-ABL仍然是一个关键的药物靶点。在此，我们研究了一种新型小分子抑制剂OGP46对K562以及一组稳定表达野生型BCR-ABL或其突变形式（包括T315I）的小鼠BaF3细胞系的抑制活性。OGP46对包括T315I在内的伊马替尼耐药BCR-ABL突变具有强大的活性。OGP46诱导细胞分化，同时伴有G0/G1期细胞周期阻滞，并抑制细胞的集落形成能力。用OGP46处理可显著降低K562和BaF3-p210-T315I细胞中BCR-ABL的mRNA和蛋白表达。从机制上讲，OGP46通过细胞分化诱导的抗癌活性可能是通过CML细胞中天然BCR-ABL和突变型BCR-ABL（包括T315I）的BCR-ABL/JAK-STAT途径实现的。我们的研究结果表明，OGP46不仅对天然BCR-ABL有活性，而且对11种临床相关的BCR-ABL突变（包括对伊马替尼耐药的T315I突变）也有活性。因此，OGP46可能是克服包括T315I在内的伊马替尼耐药BCR-ABL突变的一种新策略。
