Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; School of Chinese Materia Medica, Beijing University of Chinese Medicine, Chaoyang District, Beijing 102488, China.
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 102488, China.
Bioorg Chem. 2022 Apr;121:105699. doi: 10.1016/j.bioorg.2022.105699. Epub 2022 Feb 22.
AZD9291, with excellent pharmaceutical properties, has been reported to have certain LSD1 inhibitory activity. Therefore, we carried out structural optimization based on the AZD9291 skeleton to increase the LSD1 inhibitory potential of the compound. Then, a series of 2-aminopyrimidine derivatives were designed and synthesized as LSD1 inhibitors, and their structure-activity relationships were studied. The most promising compound, X43, with an IC of 0.89 μM showed remarkable LSD1 selectivity not only to EGFR (>100-fold) but also to MAO-A/B (>50-fold). Further studies showed that X43 inhibited LSD1 activity and induced the apoptosis of A549 cells in a dose-dependent manner. Meanwhile, compound X43 showed a superior ability to inhibit the proliferation of A549 and THP-1 cells, with IC values of 1.62 μM and 1.21 μM, respectively. Then, analyses of the stability of human liver microsomes, CYP inhibition and in vivo pharmacokinetics in rats showed that X43 had favorable profiles in vitro and in vivo and the potential for further study. Our findings suggested that a 2-aminopyrimidine-based LSD1 inhibitor deserves further investigation as a treatment for LSD1-overexpressing cancer.
AZD9291 具有优良的药学性质，据报道具有一定的 LSD1 抑制活性。因此，我们在 AZD9291 骨架的基础上进行了结构优化，以提高化合物对 LSD1 的抑制潜力。然后，我们设计并合成了一系列 2-氨基嘧啶衍生物作为 LSD1 抑制剂，并研究了它们的构效关系。最有前途的化合物 X43 的 IC 为 0.89 μM，对 LSD1 具有显著的选择性，不仅对 EGFR（>100 倍），而且对 MAO-A/B（>50 倍）也有选择性。进一步的研究表明，X43 能够抑制 LSD1 活性，并以剂量依赖的方式诱导 A549 细胞凋亡。同时，化合物 X43 表现出抑制 A549 和 THP-1 细胞增殖的优异能力，IC 值分别为 1.62 μM 和 1.21 μM。然后，对人肝微粒体的稳定性、CYP 抑制和大鼠体内药代动力学进行分析表明，X43 在体外和体内均具有良好的特性，具有进一步研究的潜力。我们的研究结果表明，基于 2-氨基嘧啶的 LSD1 抑制剂值得进一步研究，作为治疗 LSD1 过表达癌症的药物。
