School of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
Discovery Sciences IMED Biotech Unit, AstraZeneca, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
J Am Chem Soc. 2024 Apr 3;146(13):8877-8886. doi: 10.1021/jacs.3c10508. Epub 2024 Mar 19.
Hypoxia inducible factor (HIF) is a heterodimeric transcription factor composed of an oxygen-regulated α subunit and a constitutively expressed β subunit that serves as the master regulator of the cellular response to low oxygen concentrations. The HIF transcription factor senses and responds to hypoxia by significantly altering transcription and reprogramming cells to enable adaptation to a hypoxic microenvironment. Given the central role played by HIF in the survival and growth of tumors in hypoxia, inhibition of this transcription factor serves as a potential therapeutic approach for treating a variety of cancers. Here, we report the identification, optimization, and characterization of a series of cyclic peptides that disrupt the function of HIF-1 and HIF-2 transcription factors by inhibiting the interaction of both HIF-1α and HIF-2α with HIF-1β. These compounds are shown to bind to HIF-α and disrupt the protein-protein interaction between the α and β subunits of the transcription factor, resulting in disruption of hypoxia-response signaling by our lead molecule in several cancer cell lines.
缺氧诱导因子 (HIF) 是一种异二聚体转录因子，由氧调节的α亚基和组成型表达的β亚基组成，作为细胞对低氧浓度反应的主要调节剂。HIF 转录因子通过显著改变转录和重新编程细胞来感知和响应缺氧，从而使细胞适应低氧微环境。鉴于 HIF 在缺氧肿瘤的存活和生长中发挥的核心作用，抑制这种转录因子可作为治疗多种癌症的潜在治疗方法。在这里，我们报告了一系列环状肽的鉴定、优化和表征，这些环状肽通过抑制 HIF-1α 和 HIF-2α 与 HIF-1β 的相互作用，破坏 HIF-1 和 HIF-2 转录因子的功能。这些化合物被证明与 HIF-α结合，并破坏转录因子的α和β亚基之间的蛋白-蛋白相互作用，导致我们的先导分子在几种癌细胞系中破坏缺氧反应信号。
