Coulson Megan E, Norris James K S, Smith Sean A, Smalley Joshua P, Schwabe John W R, Cowley Shaun M, Hodgkinson James T
Leicester Institute of Structural and Chemical Biology and School of Chemistry, University of Leicester University Road Leicester LE1 7RH UK
Department of Molecular and Cell Biology, University of Leicester Leicester LE1 9HN UK
RSC Med Chem. 2025 Aug 5. doi: 10.1039/d5md00420a.
Lysine-specific histone demethylase 1A (LSD1) is involved in epigenetic regulation and is a viable drug target with a number of LSD1 inhibitors in clinical trials. We report synthetic and structure-activity studies of two LSD1 inhibitors, TCP and SP2577, in clinical trials towards PROTAC development. 16 Heterobifunctional molecules were synthesised based on TCP and SP2577. No LSD1 degraders were identified in HCT116 cells, however two TCP analogues functionalised from the phenyl ring with an aklyl and PEG linker in combination with a VHL ligand demonstrated potent LSD1 inhibition in the HDAC1-CoREST-LSD1 complex (43 nM and 63 nM respectively). Our findings provide important SAR data towards LSD1 PROTACs.
赖氨酸特异性组蛋白去甲基化酶1A（LSD1）参与表观遗传调控，是一个可行的药物靶点，目前有多种LSD1抑制剂正处于临床试验阶段。我们报告了两种LSD1抑制剂TCP和SP2577在用于PROTAC开发的临床试验中的合成及构效关系研究。基于TCP和SP2577合成了16种异双功能分子。在HCT116细胞中未鉴定出LSD1降解剂，然而，两种从苯环用烷基和聚乙二醇接头功能化并与VHL配体结合的TCP类似物在HDAC1-CoREST-LSD1复合物中表现出强效的LSD1抑制作用（分别为43 nM和63 nM）。我们的研究结果为LSD1 PROTACs提供了重要的构效关系数据。
