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

Wang, Yingcai1,4; Nie, Guangli1; Wang, Xingshun2,3; Ge, Wei2; Zhang, Yandong1,5

2023-11-15

10.1016/j.bmcl.2023.129505

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   Impact Factor & Quartile

0960-894X

1464-3405

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.

DHX33 RNA helicase Inhibitor high throughput screening (HTS) Cancer

SCI

English

Others

Pharmacology & Pharmacy ; Chemistry

Chemistry, Medicinal ; Chemistry, Organic

WOS:001093024600001

PERGAMON-ELSEVIER SCIENCE LTD

Web of Science

1.Shenzhen KeYe Life Technol Co Ltd, Shenzhen 518000, Guangdong, Peoples R China
2.Univ Macau, Fac Hlth Sci, Taipa, Macau, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen, Peoples R China
4.Acme Biosci Inc, Palo Alto, CA 94303 USA
5.Shenzhen KeYe Life Technol Co Ltd, Room 501,Bldg 3,Salubris Pharmaceut & Biomed Ind P, Shenzhen 518000, Guangdong, Peoples R China

Wang, Yingcai,Nie, Guangli,Wang, Xingshun,et al. Development of small molecule inhibitors targeting RNA helicase DHX33 as anti-cancer agents[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2023,96.

Wang, Yingcai,Nie, Guangli,Wang, Xingshun,Ge, Wei,&Zhang, Yandong.(2023).Development of small molecule inhibitors targeting RNA helicase DHX33 as anti-cancer agents.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,96.

Wang, Yingcai,et al."Development of small molecule inhibitors targeting RNA helicase DHX33 as anti-cancer agents".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 96(2023).