Gehling Victor S, McGrath John P, Duplessis Martin, Khanna Avinash, Brucelle Francois, Vaswani Rishi G, Côté Alexandre, Stuckey Jacob, Watson Venita, Cummings Richard T, Balasubramanian Srividya, Iyer Priyadarshini, Sawant Priyanka, Good Andrew C, Albrecht Brian K, Harmange Jean-Christophe, Audia James E, Bellon Steven F, Trojer Patrick, Levell Julian R
Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
ACS Med Chem Lett. 2020 May 6;11(6):1213-1220. doi: 10.1021/acsmedchemlett.0c00060. eCollection 2020 Jun 11.
Leveraging the catalytic machinery of LSD1 (KDM1A), a series of covalent styrenylcyclopropane LSD1 inhibitors were identified. These inhibitors represent a new class of mechanism-based inhibitors that target and covalently label the FAD cofactor of LSD1. The series was rapidly progressed to potent biochemical and cellular LSD1 inhibitors with good physical properties. This effort resulted in the identification of , a highly potent (<4 nM biochemical, 2 nM cell, and 1 nM GI), and selective LSD1 inhibitor. In-depth kinetic profiling of confirmed its covalent mechanism of action, validated the styrenylcyclopropane as an FAD-directed warhead, and demonstrated that the potency of this inhibitor is driven by improved non-covalent binding ( ). demonstrated robust cell-killing activity in a panel of AML cell lines and robust antitumor activity in a Kasumi-1 xenograft model of AML when dosed orally at 1.5 mg/kg once daily.
利用赖氨酸特异性去甲基化酶1（KDM1A）的催化机制，鉴定出了一系列共价苯乙烯基环丙烷赖氨酸特异性去甲基化酶1抑制剂。这些抑制剂代表了一类新型的基于机制的抑制剂，它们靶向并共价标记赖氨酸特异性去甲基化酶1的黄素腺嘌呤二核苷酸（FAD）辅因子。该系列化合物迅速发展成为具有良好物理性质的强效生化和细胞赖氨酸特异性去甲基化酶1抑制剂。这项工作导致鉴定出一种高效（生化活性<4 nM，细胞活性2 nM，生长抑制活性1 nM）且具有选择性的赖氨酸特异性去甲基化酶1抑制剂。对该抑制剂的深入动力学分析证实了其共价作用机制，验证了苯乙烯基环丙烷作为FAD导向弹头的作用，并表明该抑制剂的效力是由改善的非共价结合驱动的（相关内容）。在一组急性髓系白血病（AML）细胞系中，该抑制剂表现出强大的细胞杀伤活性，并且在AML的Kasumi-1异种移植模型中，当以1.5 mg/kg的剂量每日口服一次时，表现出强大的抗肿瘤活性。
