High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, PR China; University of Science and Technology of China, Hefei, Anhui 230036, PR China.
High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, PR China; CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei Anhui 230031, PR China.
Eur J Med Chem. 2017 Sep 8;137:545-557. doi: 10.1016/j.ejmech.2017.06.016. Epub 2017 Jun 9.
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, including 6 (QL-X-138), 7 (BMX-IN-1) and 8 (QL47). These studies led to the discovery of the novel potent irreversible BTK inhibitor, compound 18 (CHMFL-BTK-11). Kinetic analysis of compound 18 revealed an irreversible binding efficacy (k/K) of 0.01 μMs. Compound 18 potently inhibited BTK kinase Y223 auto-phosphorylation (EC < 100 nM), arrested cell cycle in G0/G1 phase, and induced apoptosis in Ramos, MOLM13 and Pfeiffer cells. We believe these features would make 18 a good pharmacological tool for studying BTK-related pathologies.
通过基于结构的药物设计方法，三环苯并萘啶酮药效团被用作起点，进行详细的药用结构活性关系（SAR）研究，旨在对一组拟议的 BTK 抑制剂进行特征描述，包括 6（QL-X-138）、7（BMX-IN-1）和 8（QL47）。这些研究导致发现了新型强效不可逆 BTK 抑制剂化合物 18（CHMFL-BTK-11）。化合物 18 的动力学分析显示出不可逆的结合效力（k/K）为 0.01 μMs。化合物 18 能够强烈抑制 BTK 激酶 Y223 自身磷酸化（EC < 100 nM），使 Ramos、MOLM13 和 Pfeiffer 细胞停滞在 G0/G1 期，并诱导细胞凋亡。我们相信这些特性将使 18 成为研究 BTK 相关病理学的良好药理学工具。
