2. Academic Validation
  3. Adamantaniline Derivatives Target ATP5B to Inhibit Translation of Hypoxia Inducible Factor-1α

Adamantaniline Derivatives Target ATP5B to Inhibit Translation of Hypoxia Inducible Factor-1α

  • Adv Sci (Weinh). 2023 Jul 3;e2301071. doi: 10.1002/advs.202301071.
Huiti Li 1,  Yali Liu 2,  Zian Xue 1,  Li Zhang 3,  Xiaoxue Ruan 1,  Jintong Yang 1,  Zhongjiao Fan 1,  Hongfang Zhao 2,  Yu Cao 3,  Guoqiang Chen 2,  Ying Xu 4,  Lu Zhou 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.
  • 2 Institute of Aging & Tissue Regeneration, National Key Laboratory of Cancer Systems Medicine and Chinese Academy of Medical Sciences Research Unit (NO.2019RU043), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 3 Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Shanghai, 200125, China.
  • 4 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
PMID: 37401167 DOI: 10.1002/advs.202301071
Abstract

Hypoxia inducible factor-1α (HIF-1α) plays a critical role in cellular adaptation to hypoxia and it is a potential therapeutic target for anti-cancer drugs. Applying high-throughput screening, here it is found that HI-101, a small molecule containing an adamantaniline moiety, effectively reduces HIF-1α protein expression. With the compound as a hit, a probe (HI-102) is developed for target identification by affinity-based protein profiling. The catalytic β subunit of mitochondrial FO F1 -ATP synthase, ATP5B, is identified as the binding protein of HI-derivatives. Mechanistically, HI-101 promotes the binding of HIF-1α mRNA to ATP5B, thus inhibiting HIF-1α translation and the following transcriptional activity. Further modifications of HI-101 lead to HI-104, a compound with good pharmacokinetic properties, exhibiting antitumor activity in MHCC97-L mice xenograft model, and HI-105, the most potent compound with an IC50 of 26 nm. The findings provide a new strategy for further developing HIF-1α inhibitors by translational inhibition through ATP5B.

Keywords

ATP5B; HIF-1α; adamantaniline derivatives; target identification.

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