Abstract 6777: Targeting HIF-2a pathway with a novel and potent ARNT molecular glue degrader for the treatment of renal cell carcinoma

Abstract Clear-cell renal cell carcinoma (ccRCC) is often characterized by the inactivation of the von Hippel-Lindau (VHL) gene, leading to the stabilization of hypoxia-inducible factor-2α (HIF-2α) and HIF-1α. HIF-2/1α drive expression of key oncogenic pathway genes involved in angiogenesis, proliferation, metastasis, and tumor immunity; vascular endothelial growth factor (VEGF) being one of these genes. Aryl hydrocarbon receptor nuclear translocator (ARNT), also known as hypoxia-inducible factor-1β (HIF-1β), forms heterodimers with HIF-1/2α and plays an integral role in driving HIF mediated target gene expression. Current therapies targeting HIF-2α in ccRCC and VHL diseases have shown good anti-cancer activity in the clinic. Here we describe NEO-811, an orally bioavailable, potent, selective, cereblon (CRBN)-dependent molecular glue degrader of ARNT as a novel way to target this key pathway in disease progression. NEO-811 showed dose proportional plasma exposure and good bioavailability in mice. Utilizing 786-O xenografts, a human VHL-deficient ccRCC cell line, we show NEO-811 demonstrated deep and sustained degradation of ARNT and modulation of HIF-2α target genes, VEGF and NDRG1. We observed robust efficacy after daily oral dosing of mice bearing 786-O xenografts and showed that NEO-811 was well tolerated and displayed dose dependent tumor regression. Tumor growth inhibition of 786-O xenografts with our ARNT degrader was comparable to treatment with a HIF-2α inhibitor. Importantly, NEO-811 still retained activity in 786-O xenografts that expressed a HIF-2α mutant (i.e., G323E) that conferred resistance to inhibitors. These data provide preclinical evidence and scientific rationale to further investigate NEO-811, a potent and selective ARNT molecular glue degrader, clinically in patients with ccRCC VHL deficient tumors. Citation Format: Jake Fathman, Celin Sanchez, Nathalia Cruz, Zac Naiman, J. Scott Lee, Michelle Cruz, Isabella Tran, Kevin Chiu, Jennifer Griffin, Andres Hernandez, Kurt Januszyk, Xiaoxi Liu, Bryan Lee, Anthony Burt, John Tellew, Mengyu Wu, Leslie Watson, Ana Dominguez-Andres, Ling Huang, Randy Soriano, Devin Knece, Molly FitzGibbon, Ana Grant, Mary Matyskiela, Rohan Beckwith, Klaus Wagner, Ben Wen, Phil Chamberlain. Targeting HIF-2a pathway with a novel and potent ARNT molecular glue degrader for the treatment of renal cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6777.