Abstract B090: Partially open conformation of the G323E mutated HIF-2α PASB domain captured by X-ray crystallography

作者：Steven Shia, Ian Malgapo, Jeffrey Chen, Amber Pham, Cesar Meleza, Lunda Shen, Mariya Morar, Kenneth V. Lawson, Kelsey E Sivick Gauthier, Hyock Joo Kwon · 发表于：Molecular Cancer Therapeutics · 年份：2023 · DOI：10.1158/1535-7163.targ-23-b090 · 被引用次数：1 · 研究领域：Cancer, Hypoxia, and Metabolism、Cancer-related Molecular Pathways、Ubiquitin and proteasome pathways

Abstract Under hypoxic conditions, vital cell processes such as angiogenesis, erythropoiesis, cell proliferation and metabolism are regulated by a group of transcription factors known as hypoxia-inducible factors (HIFs). These proteins belong to the helix-loop-helix family of transcription factors and require heterodimerization to function. Constitutively expressed HIF-1β protein forms a heterodimer with one of the oxygen-labile counterparts: HIF-1α, HIF-2α, or HIF-3α. The HIF-αs are degraded under normoxic conditions via ubiquitination by the von Hippel Lindau (VHL) E3 ubiquitin ligase and become available for dimerization under either hypoxia or VHL dysfunction. Certain cancer types take advantage of this HIF-regulated transcription for survival and growth, as exemplified by VHL-deficient clear cell renal cell carcinoma (ccRCC). Inhibitors aimed at disruption of the HIF-1β:HIF-2α heterodimer have been advanced into clinical development, including belzutifan (approved by the Food and Drug Administration for adult patients with VHL disease who require therapy for RCC among other indications) and AB521 (Arcus Biosciences). This class of small molecules functions by binding to and causing a conformational change in the internal cavity of the PasB domain of HIF-2α. A mutation within this internal cavity, G323E, was reported in a patient undergoing treatment with HIF-2α inhibitor. This mutation restored the ability of HIF-1β to heterodimerize with HIF-2α in presence of the inhibi...