Design and Synthesis of Styrenylcyclopropylamine LSD1 Inhibitors.

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Lysine-specific demethylase 1 (LSD1/KDM1A) is a crucial epigenetic regulator implicated in various cancers.
• Targeting LSD1 offers a therapeutic strategy for diseases driven by aberrant gene expression.

Purpose of the Study:

• To identify and characterize novel, potent, and selective covalent inhibitors of LSD1.
• To evaluate the preclinical efficacy of a lead compound in acute myeloid leukemia (AML) models.

Main Methods:

• Design and synthesis of styrenylcyclopropane-based covalent inhibitors targeting the FAD cofactor of LSD1.
• Biochemical and cellular assays to determine inhibitor potency and selectivity.
• Kinetic profiling to elucidate the mechanism of action.
• In vivo studies using AML xenograft models.

Main Results:

• Identification of a new class of mechanism-based covalent LSD1 inhibitors.
• Compound 34 emerged as a highly potent (<4 nM biochemical, 2 nM cell, 1 nM GI50) and selective inhibitor.
• Compound 34 demonstrated potent cell-killing activity in AML cell lines.
• Oral administration of compound 34 showed significant antitumor activity in a Kasumi-1 AML xenograft model.

Conclusions:

• Styrenylcyclopropane derivatives represent a viable covalent warhead for targeting LSD1.
• Compound 34 is a promising drug candidate for AML treatment.
• The study validates LSD1 as a therapeutic target and highlights the potential of covalent inhibitors.