2. Academic Validation
  3. Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles

Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles

  • ACS Med Chem Lett. 2022 Apr 29;13(5):848-854. doi: 10.1021/acsmedchemlett.2c00120.
Yasuko Koda 1,  Shin Sato 2 3,  Hirofumi Yamamoto 1,  Hideaki Niwa 2 3,  Hisami Watanabe 2 3,  Chiduru Watanabe 4,  Tomohiro Sato 4,  Kana Nakamura 3,  Akiko Tanaka 3,  Mikako Shirouzu 3,  Teruki Honma 4,  Takehiro Fukami 5,  Hiroo Koyama 1,  Takashi Umehara 2 3
Affiliations

Affiliations

  • 1 Drug Discovery Chemistry Platform Unit, Drug Discovery Seed Compounds Exploratory Unit, Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 2 Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
  • 3 Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamic Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • 4 Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
  • 5 RIKEN Program for Drug Discovery and Medical Technology Platforms, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
PMID: 35586426 DOI: 10.1021/acsmedchemlett.2c00120
Abstract

Lysine-specific demethylase 1 (LSD1/KDM1A) is a promising therapeutic target for the treatment of cancers. Several derivatives of tranylcypromine (trans-2-phenylcyclopropylamine) have been developed as LSD1 inhibitors. One such derivative is S2157; however, this compound has a high hERG channel inhibitory activity and a low microsomal stability, making it unsuitable as a drug candidate. Here, using an in silico hERG inhibition prediction model, we designed, synthesized, and evaluated a novel series of S2157 derivatives characterized by modifications of the benzyloxy and piperazine groups. Among the synthesized derivatives, a compound possessing 2-fluoropyridine and 2,8-diaza-spiro[4.5]decane groups (compound 10) showed the most desirable activities, and its eutomer, S1427, was isolated by the optical resolution of 10. In addition to potent LSD1 inhibitory activity, S1427 exhibited desirable hERG channel inhibition and microsomal stability profiles.

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