Department of Cell, Developmental and Cancer Biology, Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97201, United States.
Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California 94305, United States.
J Med Chem. 2022 Aug 25;65(16):10898-10919. doi: 10.1021/acs.jmedchem.1c01853. Epub 2022 Aug 9.
Development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene constitutes an effective approach for the treatment of chronic myeloid leukemia (CML) and/or acute lymphoblastic leukemia. However, currently available inhibitors are limited by drug resistance and toxicity. Ponatinib, a third-generation inhibitor, has demonstrated excellent efficacy against both wild type and mutant BCR-ABL kinase, including the "gatekeeper" T315I mutation that is resistant to all other currently available TKIs. However, it is one of the most cardiotoxic of the FDA-approved TKIs. Herein, we report the structure-guided design of a novel series of potent BCR-ABL inhibitors, particularly for the T315I mutation. Our drug design paradigm was coupled to iPSC-cardiomyocyte models. Systematic structure-activity relationship studies identified two compounds, and , that significantly inhibit the kinase activity of both native BCR-ABL and the T315I mutant. We have identified the most cardiac-safe TKIs reported to date, and they may be used to effectively treat CML patients with the T315I mutation.
针对 BCR-ABL 癌基因的酪氨酸激酶抑制剂 (TKI) 的开发是治疗慢性髓性白血病 (CML) 和/或急性淋巴细胞白血病的有效方法。然而，目前可用的抑制剂受到耐药性和毒性的限制。第三代抑制剂 ponatinib 对野生型和突变型 BCR-ABL 激酶均显示出优异的疗效，包括对所有其他目前可用的 TKI 均具有耐药性的“守门员”T315I 突变。然而，它是 FDA 批准的 TKI 中最具心脏毒性的药物之一。在此，我们报告了一系列新型强效 BCR-ABL 抑制剂的结构导向设计，特别是针对 T315I 突变。我们的药物设计范例与 iPSC-心肌细胞模型相结合。系统的构效关系研究确定了两种化合物 和 ，它们可显著抑制天然 BCR-ABL 和 T315I 突变体的激酶活性。我们已经确定了迄今为止报道的最具心脏安全性的 TKI，它们可用于有效治疗携带 T315I 突变的 CML 患者。
