2. Academic Validation
  3. Tying up tranylcypromine: Novel selective histone lysine specific demethylase 1 (LSD1) inhibitors

Tying up tranylcypromine: Novel selective histone lysine specific demethylase 1 (LSD1) inhibitors

  • Eur J Med Chem. 2017 Dec 1:141:101-112. doi: 10.1016/j.ejmech.2017.09.073.
Yue-Yang Ji 1,  Sen-Dong Lin 1,  Yu-Jie Wang 2,  Ming-Bo Su 2,  Wei Zhang 1,  Hendra Gunosewoyo 3,  Fan Yang 1,  Jia Li 2,  Jie Tang 4,  Yu-Bo Zhou 5,  Li-Fang Yu 6
Affiliations

Affiliations

  • 1 East China Normal University, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, 3663 North Zhongshan Road, Shanghai, 200062, China.
  • 2 National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China.
  • 3 School of Pharmacy, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia.
  • 4 Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
  • 5 National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China. Electronic address: ybzhou@simm.ac.cn.
  • 6 East China Normal University, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, 3663 North Zhongshan Road, Shanghai, 200062, China. Electronic address: lfyu@sat.ecnu.edu.cn.
PMID: 29031059 DOI: 10.1016/j.ejmech.2017.09.073
Abstract

Aberrant expression of lysine specific Histone Demethylase 1 (LSD1) has been increasingly associated with numerous Cancer cells and several proof-of-concept studies are strongly suggestive of its potential as a druggable target. Tranylcypromine (TCP) is an antidepressant originally known to target the monoamine oxidases A and B (MAO-A and MAO-B), which are structurally related to LSD1. A number of TCP derivatives have been identified as potent LSD1 inhibitors, with a handful of them currently being tested in clinical trials. However, thus far the majority of structure-activity relationship studies reported on these TCP derivatives have been mostly limited to the racemates. In this study, we present the SAR data for a novel series of conformationally-restricted TCP-based LSD1 inhibitors, both in their racemic and enantiomerically pure forms. Compounds 18b and 19b were identified as the most potent LSD1 inhibitors within this series, possessing excellent selectivity (>10,000-fold) against MAO-A and MAO-B. These compounds activated CD86 expression on the human MV4-11 AML cells following 10 days of exposure, accompanied with the apparent cytotoxicity. Taken together, these findings are consistent with the pharmacological inhibition of LSD1 and further provide structural insights on the binding modes of these TCP derivatives and their enantiomers at the LSD1.

Keywords

Chiral synthesis; LSD1; MAO-A; MAO-B; Stereoselective cyclopropanation; Tranylcypromine.

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