Vianello Paola, Sartori Luca, Amigoni Federica, Cappa Anna, Fagá Giovanni, Fattori Raimondo, Legnaghi Elena, Ciossani Giuseppe, Mattevi Andrea, Meroni Giuseppe, Moretti Loris, Cecatiello Valentina, Pasqualato Sebastiano, Romussi Alessia, Thaler Florian, Trifiró Paolo, Villa Manuela, Botrugno Oronza A, Dessanti Paola, Minucci Saverio, Vultaggio Stefania, Zagarrí Elisa, Varasi Mario, Mercurio Ciro
Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
Department of Biology and Biotechnology, University of Pavia , Via Ferrata 1, 27100 Pavia, Italy.
J Med Chem. 2017 Mar 9;60(5):1693-1715. doi: 10.1021/acs.jmedchem.6b01019. Epub 2017 Feb 27.
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.
组蛋白H3赖氨酸4（H3K4）甲基化水平的平衡由KDM1A（LSD1）调节。KDM1A在多种肿瘤类型中过表达，因此成为新型癌症治疗药物开发的一个新兴靶点。我们之前已经描述过（第1部分，DOI 10.1021.acs.jmedchem.6b01018）噻吩并[3,2-b]吡咯-5-甲酰胺作为KDM1A新型可逆抑制剂的鉴定，其初步探索得到了生化IC = 160 nM的化合物2。我们现在报告基于多个配体/KDM1A-CoRest共晶体结构对该化学系列进行的结构导向优化，这产生了几种极具活性的抑制剂。特别是，化合物46、49和50在体外抑制KDM1A时表现出个位数纳摩尔的IC值，在二级试验中具有高选择性。在THP-1细胞中，这些化合物转录影响了由KDM1A调节的基因如CD14、CD11b和CD86的表达。此外，49和50对MLL-AF9人白血病细胞表现出显著的抗克隆细胞生长作用。
