2. Academic Validation
  3. Annual review of lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors in 2021

Annual review of lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors in 2021

  • Eur J Med Chem. 2022 Jan 15:228:114042. doi: 10.1016/j.ejmech.2021.114042.
Yihui Song 1,  Huiqing Zhang 2,  Xiaoke Yang 2,  Yuting Shi 2,  Bin Yu 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, 450001, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100000, China.
  • 2 School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, 450001, China.
  • 3 School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, 450001, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100000, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. Electronic address: zzuyubin@hotmail.com.
PMID: 34915312 DOI: 10.1016/j.ejmech.2021.114042
Abstract

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising epigenetic target for disease treatment. Several LSD1 inhibitors have advanced into clinical trials. Following our last annual review on LSD1 inhibitors in 2020 (Eur. J. Med. Chem. 2021, 214, 113254), in this review we aim to update LSD1 inhibitors including natural products, synthetic compounds and cyclic peptides reported during 2021. Design strategies, structure-activity relationships, binding model analysis and modes of action are highlighted. In particular, two FDA-approved antihypertensive drugs raloxifene and fenoldopam were repurposed as reversible LSD1 inhibitors. The clinical candidate TAK-418 for treating neurodevelopmental disorders and PET imaging agent [18F]30 for LSD1 were identified. Moreover, dual inhibitors targeting both LSD1 and HDAC6 or tubulin displayed enhanced anti-cancer effects than single agents. These compounds further enrich the structural types of LSD1 inhibitors.

Keywords

Epigenetics; Histone demethylase; LSD1 inhibitors.

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