Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Bioorg Med Chem. 2020 Dec 1;28(23):115811. doi: 10.1016/j.bmc.2020.115811. Epub 2020 Oct 10.
'precision medicine' is characterized by the selection of targeted drugs based on genetic characteristics of tumor from patients, and no longer selected basis on the type of cancer tissue. Among them, clinical trials on neurotrophin receptor tyrosine kinase genes (NTRK) have proven that great anti-cancer effects can be achieved in different cancer patients. In this paper, a novel total of twenty compounds in two categories have been designed and synthesized. Results of Kinase activity tests showed that I-9 (TRKA IC = 1.3 nM, TRKA IC = 6.1 nM), and I-10 (TRKA IC = 1.1 nM, TRKA IC = 5.3 nM) have significant inhibitory activity, and results of cell viability tests showed that I-9 and I-10 can maintain a great inhibitory effect in the Ba/F3-LMNA-NTRK1 cell line(IC = 81.1 nM and 41.7 nM, respectively), and in Ba/F3-LMNA-NTRK1-G595R cell line, I-9 and I-10 have better cell activity (IC was 495.3 nM, 336.6 nM, respectively) compared with the positive control drug LOXO-101. These results indicate that I-9 and I-10 are potential TRK inhibitors that can overcome drug resistance for further investigation.
“精准医学”的特点是以肿瘤患者的基因特征为依据选择靶向药物，而不再依据癌症组织的类型进行选择。其中，神经生长因子受体酪氨酸激酶基因（NTRK）的临床试验已证明，不同癌症患者都能取得很好的抗癌效果。本文设计并合成了两类共二十种新化合物。激酶活性测试结果表明，化合物 I-9（TRKA IC = 1.3 nM，TRKA IC = 6.1 nM）和 I-10（TRKA IC = 1.1 nM，TRKA IC = 5.3 nM）具有显著的抑制活性，细胞活力测试结果表明，I-9 和 I-10 可在 Ba/F3-LMNA-NTRK1 细胞系中保持很强的抑制作用（IC 值分别为 81.1 nM 和 41.7 nM），在 Ba/F3-LMNA-NTRK1-G595R 细胞系中，I-9 和 I-10 的细胞活性优于阳性对照药物 LOXO-101（IC 值分别为 495.3 nM 和 336.6 nM）。这些结果表明，I-9 和 I-10 是具有潜力的 TRK 抑制剂，可以克服耐药性，值得进一步研究。
