Li Chunpu, Su Mingbo, Zhu Wei, Kan Weijuan, Ge Tianpeng, Xu Gaoya, Wang Shuni, Sheng Li, Gao Feng, Ye Yunfei, Wang Jiang, Zhou Yubo, Li Jia, Liu Hong
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
J Med Chem. 2022 Mar 10;65(5):4335-4349. doi: 10.1021/acs.jmedchem.1c02156. Epub 2022 Feb 24.
LSD1 is identified as an essential drug target, which is closely correlated to the development of several tumor types. In this work, on the basis of comprehensive analysis of the binding site of LSD1 and other FAD-dependent enzymes, a novel series of potent and selective LSD1 inhibitors were designed by incorporation of privileged indoline scaffold strategies. Representative compound (LSD1; IC = 24.43 nM, selectivity over LSD2 and MAOs of >200- and 4000-fold) possessed selective antiproliferative activities against MV-4-11 cell lines. Further study indicates that could activate CD86 expression (EC = 470 nM) and induce differentiation of AML cell lines. More importantly, compound demonstrated an acceptable oral PK profile and good antitumor efficacy with a / value of 30.89% in an MV-4-11 xenograft mouse model. Collectively, this work provides a promising lead compound for the development of novel LSD1 inhibitors for the treatment of AML.
赖氨酸特异性去甲基化酶1（LSD1）被确定为一种重要的药物靶点，它与多种肿瘤类型的发展密切相关。在这项工作中，基于对LSD1与其他黄素腺嘌呤二核苷酸（FAD）依赖性酶结合位点的综合分析，通过引入具有优势的吲哚啉骨架策略，设计了一系列新型的强效且选择性的LSD1抑制剂。代表性化合物（对LSD1的半数抑制浓度[IC] = 24.43 nM，对LSD2和单胺氧化酶的选择性分别超过200倍和4000倍）对MV-4-11细胞系具有选择性抗增殖活性。进一步研究表明，该化合物可激活CD86表达（半数有效浓度[EC] = 470 nM）并诱导急性髓系白血病（AML）细胞系分化。更重要的是，在MV-4-11异种移植小鼠模型中，该化合物显示出可接受的口服药代动力学特征和良好的抗肿瘤疗效，肿瘤抑制率为30.89%。总的来说，这项工作为开发用于治疗AML的新型LSD1抑制剂提供了一种有前景的先导化合物。
