Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Master Program in Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):226-235. doi: 10.1080/14756366.2021.1999237.
Bruton tyrosine kinase (BTK) is linked to multiple signalling pathways that regulate cellular survival, activation, and proliferation. A covalent BTK inhibitor has shown favourable outcomes for treating B cell malignant leukaemia. However, covalent inhibitors require a high reactive warhead that may contribute to unexpected toxicity, poor selectivity, or reduced effectiveness in solid tumours. Herein, we report the identification of a novel noncovalent BTK inhibitor. The binding interactions (i.e. interactions from known BTK inhibitors) for the BTK binding site were identified and incorporated into a structure-based virtual screening (SBVS). Top-rank compounds were selected and testing revealed a BTK inhibitor with >50% inhibition at 10 µM concentration. Examining analogues revealed further BTK inhibitors. When tested across solid tumour cell lines, one inhibitor showed favourable inhibitory activity, suggesting its potential for targeting BTK malignant tumours. This inhibitor could serve as a basis for developing an effective BTK inhibitor targeting solid cancers.
布鲁顿酪氨酸激酶（BTK）与多种信号通路相关，这些通路调节细胞的存活、激活和增殖。一种共价 BTK 抑制剂已显示出对治疗 B 细胞恶性白血病的有利结果。然而，共价抑制剂需要一个高反应性的弹头，这可能导致意外的毒性、较差的选择性或在实体瘤中降低疗效。在此，我们报告了一种新型非共价 BTK 抑制剂的鉴定。鉴定了 BTK 结合位点的结合相互作用（即来自已知 BTK 抑制剂的相互作用），并将其纳入基于结构的虚拟筛选（SBVS）中。选择排名靠前的化合物进行测试，结果显示一种 BTK 抑制剂在 10μM 浓度下的抑制率超过 50%。对类似物的研究揭示了更多的 BTK 抑制剂。当在实体瘤细胞系中进行测试时，一种抑制剂显示出良好的抑制活性，这表明它有可能针对 BTK 恶性肿瘤。该抑制剂可作为开发针对实体癌的有效 BTK 抑制剂的基础。
