Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.
Department of Physiology, Life Science and Biopharmaceutical Institution, Shenyang Pharmaceutical University, Shenyang, China.
Eur J Med Chem. 2021 Aug 5;220:113501. doi: 10.1016/j.ejmech.2021.113501. Epub 2021 Apr 24.
Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. In particular, the representative compound 17i exhibited excellent LSD1 inhibition at the molecular levels with IC = 0.065 μM, as well as anti-proliferation against MCF-7, MGC-803, H460, A549 and THP-1 tumor cells with IC values of 2.90 ± 0.32, 5.85 ± 0.35, 2.06 ± 0.27, 5.74 ± 1.03 and 6.15 ± 0.49 μM, respectively. The binding modes of these compounds were rationalized by molecular docking. Meanwhile, a preliminary druggability evaluation showed that compound 17i displayed favorable liver microsomal stability and weak inhibitory activity against CYPs at 10 μM. Remarkably, H460 xenograft tumors studies revealed that 17i demonstrated robust in vivo antitumor efficacy without significant side effects. All the results demonstrated that compound 17i could represent a promising lead for further development.
赖氨酸特异性脱甲基酶 1（LSD1）是一种依赖黄素腺嘌呤二核苷酸（FAD）的酶，已被提议作为治疗癌症的有前途的靶点。在此基础上，我们基于构象限制策略，通过骨架跃迁设计、合成并对一系列苯并呋喃衍生物进行了生化评价，作为新型 LSD1 抑制剂。大多数化合物对 LSD1 的酶活性具有很强的抑制作用，并能有效抑制肿瘤细胞的增殖。特别是代表性化合物 17i 在分子水平上对 LSD1 具有优异的抑制作用，IC50 值为 0.065 μM，对 MCF-7、MGC-803、H460、A549 和 THP-1 肿瘤细胞的增殖抑制作用也很强，IC50 值分别为 2.90 ± 0.32、5.85 ± 0.35、2.06 ± 0.27、5.74 ± 1.03 和 6.15 ± 0.49 μM。通过分子对接对这些化合物的结合模式进行了合理化分析。同时，初步的药物代谢动力学评价表明，化合物 17i 在 10 μM 时对肝微粒体具有良好的稳定性，对 CYP 的抑制活性较弱。值得注意的是，H460 异种移植肿瘤研究表明，17i 表现出强大的体内抗肿瘤疗效，且无明显副作用。所有结果表明，化合物 17i 可能是进一步开发的有前途的先导化合物。
