Design and Synthesis of Styrenylcyclopropylamine LSD1 Inhibitors

Abstract

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 GI50), 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.

Tertiary sulphonamide derivatives as dual acting small molecules that inhibit LSD1 and suppress tubulin polymerisation against liver cancer

“…To determine the inhibitory effects of these tertiary sulphonamide derivative against LSD1, LSD1 enzymatic assay was performed according to reported references 15 , 16 . The enzymatic activity results of tertiary sulphonamide derivatives against LSD1 were shown in Figure 7 .…”

Discovery of orally active chalcones as histone lysine specific demethylase 1 inhibitors for the treatment of leukaemia

“…The inhibition of LSD1 activity was evaluated according to reported references [ 23 , 24 ]. pET-28b-LSD1 (full length) was transfected into BL21 (DE).…”

Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

“…[ 372 ] A study by gehling et al led to the identification of a highly potent and selective LSD 1 inhibitor, compound 111, (< 4 nM biochemical, 2 nM cell, and 1 nM GI 50 ). Compound 111 exhibited cell growth inhibitory effects in a panel of AML cell lines along with notable antitumor potential in a Kasumi-1 xenograft model of AML at the dose of 1.5 mg/kg once daily (administered orally) [ 373 ].

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