Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors
Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors
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苯并萘啶酮衍生物作为新型有效布鲁顿酪氨酸激酶（BTK）不可逆抑制剂的构效关系研究
DOI：
10.1016/j.ejmech.2017.06.016
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发表时间：
2017
影响因子：
6.7
通讯作者：
Jing Liu
中科院分区：
文献类型：
--
作者：
Beilei Wang;Yuanxin Deng;Yongfei Chen;Kailin Yu;Aoli Wang;Qianmao Liang;Wei Wang;Cheng Chen;Hong Wu;Chen Hu;Weili Miao;Wooyoung Hur;Wenchao Wang;Zhenquan Hu;Ellen L. Weisberg;Jinhua Wang;Tao Ren;Yinsheng Wang;Nathanael S. Gray;Qingsong Liu;Jing Liu
通过基于结构的药物设计方法，以三环苯并萘二酮药效基团为起点进行详细的药物构效关系(SAR)研究，旨在表征一组拟议的BTK抑制剂，包括6(QL-X-138)，7(BMX-IN-1)和8(QL47)。这些研究导致了新的有效的不可逆BTK抑制剂化合物18(CHMFL-BTK-11)的发现。对化合物18的动力学分析表明，化合物18对μM−1s−1具有不可逆的结合效率(Kinact/Ki)。化合物18能有效抑制BTK KY223的自磷酸化，使细胞周期停滞在G0/G1期，并诱导Ramos、MOLM13和Pfeiffer细胞的凋亡。我们相信，这些特点将使18成为研究BTK相关病理的很好的药理学工具。
Through a structure-based drug design approach, a tricyclic benzonaphthyridinone pharmacophore was used as a starting point for carrying out detailed medicinal structure-activity relationhip (SAR) studies geared toward characterization of a panel of proposed BTK inhibitors, including6(QL-X-138),7(BMX-IN-1) and8(QL47). These studies led to the discovery of the novel potent irreversible BTK inhibitor, compound18(CHMFL-BTK-11). Kinetic analysis of compound18revealed an irreversible binding efficacy (kinact/Ki) of 0.01 μM−1s−1. Compound18potently inhibited BTK kinase Y223 auto-phosphorylation (EC50< 100 nM), arrested cell cycle in G0/G1 phase, and induced apoptosis in Ramos, MOLM13 and Pfeiffer cells. We believe these features would make18a good pharmacological tool for studying BTK-related pathologies.