Abstract 5791: Preclinical characterization of NEO-811, a novel molecular glue degrader of ARNT for the treatment of clear cell renal cell carcinoma

Abstract A hallmark of clear cell renal cell carcinoma (ccRCC) is inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). Deficiency in VHL results in aberrant stabilization and activation of hypoxia-inducible factors 1α and 2α (HIF-1α/2α) promoting cancer cell survival, metastasis, and angiogenesis. The therapeutic value of targeting hypoxia signaling in ccRCC has been clinically validated by the development of small molecule inhibitors of HIF-2α. However, subsequent studies have also uncovered susceptibility to the onset of resistance conferred by mutations in the small molecule binding pocket. As class I basic helix-loop-helix PER/ARNT/SIM (bHLH-PAS) proteins, HIF-1α/2α require heterodimerization with aryl hydrocarbon nuclear translocator (ARNT, also known as HIF-1β, a class II bHLH-PAS protein) to exert their transcriptional activity. Consequently, ARNT represents a viable alternative target for disrupting oncogenic HIF activity. While traditionally regarded as undruggable, here we highlight the preclinical characterization of NEO-811, a potent, selective, and orally bioavailable molecular glue degrader of ARNT. Consistent with its mechanism of action, NEO-811 induced rapid, cereblon (CRBN)-dependent ARNT depletion in multiple ccRCC cell lines in vitro and in vivo. Global proteomics analysis confirmed that NEO-811 was highly selective and did not degrade well-known neosubstrates. Transcriptomic profiling of NEO-811 activity across several VHL-deficient ccRCC cell lines confirmed suppression of HIF-2α target genes, including cyclin D and vascular endothelial growth factor (VEGF). NEO-811 also uniquely suppressed expression of target genes regulated by other Class I bHLH-PAS transcription factors, including HIF-1α and aryl hydrocarbon receptor (AHR). Critically, NEO-811 retained activity in HIF-2α inhibitor-resistant cells that harbored previously described mutations. In conclusion, our findings highlight the potential of ARNT degradation as a promising therapeutic modality for the treatment of VHL-deficient ccRCC. Citation Format: J. Scott Lee, Michelle S. Cruz, Isabella Tran, Kevin Chiu, Jennifer Griffin, Andres H de la Peña, 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, Jake Fathman, Celin Sanchez, Nathalia Cruz, Zac Neiman, Ana Grant, Mary Matyskiela, Rohan Beckwith, Ben Wen, Klaus Wagner, Philip Chamberlain., . Preclinical characterization of NEO-811, a novel molecular glue degrader of ARNT for the treatment of clear cell 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 5791.