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

  • Bioorg Med Chem Lett. 2023 Oct 12:96:129505. doi: 10.1016/j.bmcl.2023.129505.
Yingcai Wang  1 ,  Guangli Nie  2 ,  Xingshun Wang  3 ,  Wei Ge  4 ,  Yandong Zhang  5
Affiliations
  • 1. Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China; Acme Bioscience, Inc, Palo Alto, CA 94303, USA.
  • 2. Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China.
  • 3. Faculty of Health Sciences, University of Macau, Taipa, Macau, China; Southern University of Science and Technology, Shenzhen 518055, China.
  • 4. Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
  • 5. Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China. Electronic address: [email protected].
PMID: 37838340 DOI: 10.1016/j.bmcl.2023.129505
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.

Keywords
Cancer; DHX33; Inhibitor; RNA helicase; high throughput screening (HTS).
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