7VQT

Crystal structure of LSD1 in complex with compound 5

Summary for 7VQT

• Entry DOI: 10.2210/pdb7vqt/pdb
• Descriptor: Lysine-specific histone demethylase 1A, GLYCEROL, L(+)-TARTARIC ACID, ... (5 entities in total)
• Functional Keywords: demethylase, amine oxidase, chromatin, histone, fad, mechanism-based inhibitor, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 75932.31

Authors

Niwa, H.,Koda, Y.,Sato, S.,Yamamoto, H.,Koyama, H.,Umehara, T. (deposition date: 2021-10-20, release date: 2022-06-01, Last modification date: 2023-11-29)

Primary citation

Koda, Y.,Sato, S.,Yamamoto, H.,Niwa, H.,Watanabe, H.,Watanabe, C.,Sato, T.,Nakamura, K.,Tanaka, A.,Shirouzu, M.,Honma, T.,Fukami, T.,Koyama, H.,Umehara, T.
Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles.
Acs Med.Chem.Lett., 13:848-854, 2022

PubMed Abstract: Lysine-specific demethylase 1 (LSD1/KDM1A) is a promising therapeutic target for the treatment of cancers. Several derivatives of tranylcypromine (2-phenylcyclopropylamine) have been developed as LSD1 inhibitors. One such derivative is ; 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 hERG inhibition prediction model, we designed, synthesized, and evaluated a novel series of 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 ) showed the most desirable activities, and its eutomer, , was isolated by the optical resolution of . In addition to potent LSD1 inhibitory activity, exhibited desirable hERG channel inhibition and microsomal stability profiles.

PubMed: 35586426
DOI: 10.1021/acsmedchemlett.2c00120

Experimental method

X-RAY DIFFRACTION (2.91 Å)