Synthesis, optimization and antitumor activity evaluation of sulfonyl benzoyl hydrazide derivatives as novel human LSD1 inhibitors

Wei Ai; Zeping Zuo

doi:10.1016/j.bmcl.2024.129982

Synthesis, optimization and antitumor activity evaluation of sulfonyl benzoyl hydrazide derivatives as novel human LSD1 inhibitors

Bioorg Med Chem Lett. 2024 Dec 1:114:129982. doi: 10.1016/j.bmcl.2024.129982. Epub 2024 Oct 9.

Authors

Wei Ai¹, Zeping Zuo²

Affiliations

¹ Laboratory of Anaesthesiology & Critical Care Medicine, Department of Anesthesiology, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
² Laboratory of Anaesthesiology & Critical Care Medicine, Department of Anesthesiology, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, PR China. Electronic address: [email protected].

PMID: 39384076
DOI: 10.1016/j.bmcl.2024.129982

Abstract

A new set of compounds known as sulfonyl benzoyl hydrazide derivatives were synthesized and tested using cellular assays. Through systematic optimization starting from general structure S-1, compound 10e emerged as highly promising. It exhibited potent inhibitory activity with an IC₅₀ value of 0.8 nM and possessed moderate clogP. Compounds 10e significantly inhibited solid tumor cells proliferation. Additionally, 10e induced apoptosis and arrested the cell cycle. Furthermore, in vivo studies using an HCT116 xenograft model showed substantial growth inhibition of tumors, accompanied by a favorable safety profile. These findings underscored compound 10e as a novel LSD1 inhibitor with robust efficacy both in vitro and in vivo, establishing it as a promising lead compound for further anticancer drug development.

Keywords: Benzoyl hydrazide derivatives; LSD1; Structure–activity relationship.

MeSH terms

Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation* / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
HCT116 Cells
Histone Demethylases* / antagonists & inhibitors
Histone Demethylases* / metabolism
Humans
Hydrazines* / chemical synthesis
Hydrazines* / chemistry
Hydrazines* / pharmacology
Mice
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
KDM1A protein, human
Histone Demethylases
Hydrazines
Enzyme Inhibitors