# Project 1: Targeting HIF-2 for the Treatment of Clear-Cell Renal Cell Carcinoma > **NIH NIH P50** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $321,476 ## Abstract Project Summary Renal cell carcinoma of clear cell type (ccRCC), the most common type, is characterized by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which is observed in >85% of tumors. Because no other gene is mutated at a similar frequency, and VHL mutations are a known initiating event, VHL loss is regarded as the governing event in ccRCC development. Loss of VHL activates HIF-2, which is sufficient to reconstitute tumor development in ccRCC cell lines restored with VHL. Arguably, HIF-2 is the most attractive target for drug development in ccRCC. HIF-2 is implicated in cell survival, proliferation, pluripotency and angiogenesis. Among these pathways, only angiogenesis is targeted clinically, today. Targeting HIF-2 would disrupt multiple pro-oncogenic pathways simultaneously, but as a transcription factor, HIF-2 is considered undruggable. HIF- 2 is an obligatory heterodimer of a constitutive HIF-1 subunitand a regulated HIF-2 subunit, which was discovered at UT Southwestern Medical Center (UTSW). Detailed structural studies of HIF-2at UTSW identified a 280Å3 cavity within the PAS-B domain, a domain implicated in heterodimerization. Despite the fact that this cavity is buried, UTSW investigators determined that it was accessible and hypothesized that it may provide a foothold for a small molecule. Such a molecule may induce conformational changes transmitted to the surface of the domain disrupting the interaction with HI F-1 and antagonizing HIF-2 function. Proof-of-principle experiments confirmed this idea and an ingenious high-throughput screen involving 200,000 compounds led to the identification of small-molecule inhibitors of HIF-2 heterodimerization. The lead compound was optimized through medicinal chemistry efforts at UTSW and was subsequently licensed to Peloton Therapeutics, Inc., a company founded by UTSW investigators and located in the UTSW BioCenter. Peloton has developed this compound into a highly-potent and selective inhibitor of HIF-2 (HIF2-I) with appropriate pharmacokinetic properties and oral bioavailability. This drug induces regression of established ccRCC cell line xenografts, and preliminary experiments show remarkable activity in some patient-derived xenografts (PDX)/tumorgraft models. However, not every ccRCC tumorgraft responds. The aims of this project are: (i) to identify a biomarker of HIF-2 dependency in ccRCC, (ii) to anticipate mechanisms of acquired resistance to HIF2-I, and (iii) to evaluate multiparametric MR imaging as a pharmacodynamic biomarker in a first-in-human phase I clinical trial of this first-in-class HIF2-I in metastatic ccRCC patients. The successful development of an inhibitor against HIF-2 serves as a paradigm for innovation. To our knowledge, this is the first isoform-specific inhibitor of a transcription factor of the non- nuclear hormone receptor family. This illustrates how ground-breaking basic science discoveries can be translate... ## Key facts - **NIH application ID:** 9990730 - **Project number:** 5P50CA196516-05 - **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER - **Principal Investigator:** James Brugarolas - **Activity code:** P50 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $321,476 - **Award type:** 5 - **Project period:** 2016-08-01 → 2022-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9990730 ## Citation > US National Institutes of Health, RePORTER application 9990730, Project 1: Targeting HIF-2 for the Treatment of Clear-Cell Renal Cell Carcinoma (5P50CA196516-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990730. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*