Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Synthetic and Functional Biomolecules Center, Beijing National Laboratory of Molecular Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Peking, 100871, P. R. China.
Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, P. R. China.
Chembiochem. 2021 Jan 5;22(1):129-133. doi: 10.1002/cbic.202000527. Epub 2020 Oct 20.
Ibrutinib is an FDA-approved drug to treat B-lymphoid malignancies, which functions mechanistically as a covalent inhibitor for Bruton's tyrosine kinase (BTK). During the course of screening more potent and selective BTK inhibitors, we discovered that MM2-48, an ibrutinib analogue that contains the alkynyl amide functional group in place of the acrylamide warhead, exhibits a much stronger cytotoxicity. Comparative chemoproteomic profiling of the targets of ibrutinib and MM2-48 revealed that the alkynyl amide warhead exhibits much higher reactivity in proteomes. Unexpectedly, MM2-48 covalently targets a functional cysteine in a BRCA2 and CDKN1A-interacting protein, BCCIP, and significantly inhibits DNA damage repair. Our findings suggest that simultaneous inhibition of BTK activity and DNA damage repair might be a more effective therapeutic strategy for combating B-cell malignancies.
伊布替尼是一种经美国食品药品监督管理局批准用于治疗 B 淋巴细胞恶性肿瘤的药物，其作用机制是作为布鲁顿酪氨酸激酶 (BTK) 的共价抑制剂。在筛选更有效和选择性的 BTK 抑制剂的过程中，我们发现 MM2-48，一种含有炔基酰胺官能团而非丙烯酰胺弹头的伊布替尼类似物，具有更强的细胞毒性。伊布替尼和 MM2-48 的靶标比较化学蛋白质组学分析表明，炔基酰胺弹头在蛋白质组中具有更高的反应性。出乎意料的是，MM2-48 共价靶向 BRCA2 和 CDKN1A 相互作用蛋白 BCCIP 中的一个功能性半胱氨酸，并显著抑制 DNA 损伤修复。我们的研究结果表明，同时抑制 BTK 活性和 DNA 损伤修复可能是对抗 B 细胞恶性肿瘤的更有效治疗策略。
