Development of small molecule inhibitors targeting RNA helicase DHX33 as anti-cancer agents.

Abstract

RNA helicase DHX33 has been identified to be a critical factor in promoting cancer development. Genetic deletion of DHX33 significantly blocks tumorigenesis. Importantly, its helicase activity was found to be pivotal for exerting cellular functions. Herein we used a helicase-based high throughput screening (HTS) to discover DHX33 inhibitors from Chembridge chemical library containing 15,000 small molecules. We identified a hit compound containing benzimidazole ring that demonstrated activity against DHX33 with certain selectivity. Further structural optimization led to the design and synthesis of a series of analog inhibitors. Considering the potential role of DHX33 in cancer development, the compounds were evaluated based on the cytotoxicity activity in U251-MG cancer cells in vitro. Among them, compound IVa (KY386) was identified to be a selective inhibitor for DHX33 helicase with potent anti-cancer activity and moderate metabolic stability. These results support the promising role of DHX33 inhibitors for development of novel anti-cancer drugs.

• Authors: Yingcai Wang, Guangli Nie, Xingshun Wang, Wei Ge, Yandong Zhang
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 96 Pg. 129505 (11 15 2023) ISSN: 1464-3405 [Electronic] England
• PMID: 37838340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents

Topics

• Antineoplastic Agents (pharmacology)