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Development of small molecule inhibitors targeting RNA helicase DHX33 as anti-cancer agents
Yingcai Wang1, Guangli Nie2, Xingshun Wang3
1Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China; Acme Bioscience, Inc, Palo Alto, CA 94303, USA.
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.
Insights
Researchers identified a novel benzimidazole compound (KY386) that selectively inhibits RNA helicase DHX33, a key factor in cancer development. This DHX33 inhibitor shows potent anti-cancer activity, offering a promising new avenue for cancer drug development.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- RNA helicase DHX33 is a critical factor in cancer development.
- DHX33's helicase activity is essential for its cellular functions.
- Genetic deletion of DHX33 significantly inhibits tumorigenesis.
Purpose of the Study:
- To discover novel DHX33 inhibitors using a helicase-based high-throughput screening.
- To identify potent anti-cancer agents targeting DHX33.
Main Methods:
- High-throughput screening (HTS) of 15,000 small molecules from the Chembridge library.
- Structure-based optimization of hit compounds.
- In vitro cytotoxicity evaluation in U251-MG cancer cells.
Main Results:
- A benzimidazole-containing compound was identified as a DHX33 inhibitor.
- Compound IVa (KY386) demonstrated selective DHX33 inhibition.
- KY386 exhibited potent anti-cancer activity and moderate metabolic stability.
Conclusions:
- DHX33 inhibitors represent a promising strategy for novel anti-cancer drug development.
- Compound KY386 is a selective DHX33 inhibitor with significant anti-cancer potential.
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