Open AccessDesign and Synthesis of Styrenylcyclopropylamine LSD1 Inhibitors
Author(s) -
Victor S. Gehling,
John P. McGrath,
Martin Duplessis,
Avinash Khanna,
François Brucelle,
Rishi G. Vaswani,
Alexandre Côté,
Jacob I. Stuckey,
Venita Gresham Watson,
Richard Cummings,
Srividya Balasubramanian,
Priyadarshini Iyer,
Priyanka Sawant,
Andrew C. Good,
Brian K. Albrecht,
Jean-Christophe Harmange,
James E. Audia,
Steven F. Bellon,
Patrick Trojer,
Julian Levell
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00060
Subject(s) - covalent bond , chemistry , potency , mechanism of action , biochemistry , cofactor , enzyme , combinatorial chemistry , pharmacology , biology , in vitro , organic chemistry
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 34 , a highly potent (<4 nM biochemical, 2 nM cell, and 1 nM GI 50 ), and selective LSD1 inhibitor. In-depth kinetic profiling of 34 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 ( K I ). 34 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.