Abstract IA009: Development of HIF2 inhibitors: Bench to bedside and back

Abstract

Abstract Arguably the most important driver of clear cell renal cell carcinoma (ccRCC), HIF2a was traditionally regarded as undruggable. However, structural analyses at UT Southwestern Medical Center found a vulnerability leading to the identification of small molecule inhibitors, and eventually the development of highly related PT drugs by Peloton Therapeutics (PT2385 and PT2977, also called belzutifan). PT drugs bind to HIF2a and induce a conformational change that triggers its dissociation from HIF1b, thereby inhibiting DNA binding and gene transactivation. PT drugs have shown activity in patients, but resistance develops over time. Resistance mutations have been identified, initially in preclinical models, and subsequently in patients. This has spurred the development of second-generation inhibitors, including siRNA-based therapeutics. Recently, we reported a tumor-directed HIF2a-targeting siRNA drug (siHIF2) developed by Arrowhead Pharmaceuticals that effectively depleted both wild-type and mutant HIF2a. siHIF2 showed activity against ccRCC in preclinical models and in patients. Overall, these studies establish HIF2a as a core dependency and therapeutic target, and set a paradigm for tumor-directed RNA-based therapeutics in cancer. Citation Format: James Brugarolas. Development of HIF2 inhibitors: Bench to bedside and back [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA009.