Structure-based design and discovery of potent and selective lysine-specific demethylase 1 (LSD1) inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 29; no. 1; pp. 103 - 106
• Main Authors: Nie, Zhe, Shi, Lihong, Lai, Chon, Severin, Christophe, Xu, Jiangchun, Del Rosario, Joselyn R., Stansfield, Ryan K., Cho, Robert W., Kanouni, Toufike, Veal, James M., Stafford, Jeffrey A., Chen, Young K.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2019; Elsevier
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Demethylase; Epigenetics; Life Sciences & Biomedicine; LSD1; Lysine-specific demethylase 1; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-based drug design; Epigenetics; Demethylase; Structure-based drug design; Lysine-specific demethylase 1; LSD1; LSD1 Structure-based drug design; REVERSIBLE INHIBITORS; DERIVATIVES
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.11.001

[Display omitted] •A series of highly potent and selective reversible LSD1 inhibitors were discovered employing structure-based drug design.•Potent induction of cellular differentiation marker CD11b in THP-1 was demonstrated with reversible LSD1 inhibitors.•Optimization of indazole analogs led to compounds with desirable potency, hERG inhibition profile, and oral PK properties. The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule reversible inhibitors of LSD1 as an attractive approach to treat hematologic malignancies and certain solid tumors. Using structure-based drug design, we designed and synthesized a novel series of heteroaromatic imidazole inhibitors that demonstrate potent inhibition of the demethylase activity and low nanomolar cell-based activity. This novel LSD1 inhibitor series was further optimized by attenuating the hERG inhibition and improving oral bioavailability.