Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China.
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.
Adv Sci (Weinh). 2023 Sep;10(25):e2301071. doi: 10.1002/advs.202301071. Epub 2023 Jul 3.
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 F F -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 IC of 26 nm. The findings provide a new strategy for further developing HIF-1α inhibitors by translational inhibition through ATP5B.
缺氧诱导因子-1α（HIF-1α）在细胞对缺氧的适应中起着关键作用，是抗癌药物的潜在治疗靶点。通过高通量筛选，发现小分子化合物 HI-101 能有效降低 HIF-1α 蛋白表达。以该化合物为先导物，通过亲和蛋白谱法开发了探针 HI-102 进行靶标鉴定。HI-衍生物的结合蛋白被鉴定为线粒体 F F -ATP 合酶的催化β亚基 ATP5B。在机制上，HI-101 促进 HIF-1α mRNA 与 ATP5B 的结合，从而抑制 HIF-1α 的翻译及其后续的转录活性。对 HI-101 的进一步修饰得到了 HI-104，一种具有良好药代动力学性质的化合物，在 MHCC97-L 小鼠异种移植模型中显示出抗肿瘤活性，以及最有效的化合物 HI-105，其 IC 为 26nm。这些发现为通过 ATP5B 翻译抑制进一步开发 HIF-1α 抑制剂提供了一种新策略。
