Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
Bioorg Chem. 2022 Feb;119:105541. doi: 10.1016/j.bioorg.2021.105541. Epub 2021 Dec 7.
Bruton's tyrosine kinase (BTK) is an attractive target for the treatment of malignancy and inflammatory/autoimmune diseases. Most of the covalent BTK inhibitors would induce off-target side effects and drug resistance. To improve the drug safety of BTK inhibitors, non-covalent inhibitors have attracted more and more attention. We designed a series of novel pyrido[3,4-b]indol-1-one derivatives (N-A and N-B) via scaffold hopping from CGI-1746. The structure-activity relationship (SAR) of the newly-synthesized compounds was explored. The results showed that compounds 12 and 18 exhibited potent enzymatic potency against BTK with IC values of 0.22 μM and 0.19 μM, respectively. In lymphoma cell lines U-937 cells and Ramos cells, compounds 12 and 18 displayed comparative antiproliferative activity with Ibrutinib. Moreover, compound 12 induced G1-phase cell cycle arrest and apoptosis in U-937 cells. And it could effectively inhibit tumor growth in U-937 xenograft mouse model (TGI = 41.90% at 50 mg/kg). In all, the new pyrido[3,4-b]indol-1-one derivatives have the antitumor potency by BTK inhibition and were worthy of further exploration.
布鲁顿酪氨酸激酶（BTK）是治疗恶性肿瘤和炎症/自身免疫性疾病的有吸引力的靶点。大多数共价 BTK 抑制剂会引起非靶标副作用和耐药性。为了提高 BTK 抑制剂的药物安全性，非共价抑制剂越来越受到关注。我们通过从 CGI-1746 进行支架跳跃设计了一系列新型吡啶并[3,4-b]吲哚-1-酮衍生物（N-A 和 N-B）。探索了新合成化合物的结构-活性关系（SAR）。结果表明，化合物 12 和 18 对 BTK 具有很强的酶抑制活性，IC 值分别为 0.22 μM 和 0.19 μM。在淋巴瘤细胞系 U-937 细胞和 Ramos 细胞中，化合物 12 和 18 与伊布替尼具有相当的抗增殖活性。此外，化合物 12 在 U-937 细胞中诱导 G1 期细胞周期停滞和凋亡。并且它可以有效地抑制 U-937 异种移植小鼠模型中的肿瘤生长（在 50mg/kg 时 TGI=41.90%）。总之，新型吡啶并[3,4-b]吲哚-1-酮衍生物通过 BTK 抑制具有抗肿瘤活性，值得进一步探索。
