Abstract ND01: Development of NEO-811, a molecular glue degrader of ARNT (HIF-1β) with potent single agent activity in ccRCC

Abstract Inactivation of Von Hippel Lindau (VHL) occurs in up to 90% of patients with clear cell renal cell carcinoma (ccRCC), leading to constitutive activation of hypoxia inducible factors, HIF-1⍺ and HIF-2⍺, and triggering a pro-tumorigenic transcriptional program (e. g. , VEGF, EPO). Thus, the HIF-2⍺ antagonist belzutifan has demonstrated beneficial clinical activity in ccRCC, gaining clinical approvals for use in patients with ccRCC as well as for VHL disease associated tumors, pheochromocytomas and paragangliomas. However, there is considerable unmet need and opportunity to improve on the existing ccRCC therapies. Aryl hydrocarbon receptor nuclear translocator (ARNT, or HIF-1β) is an undruggable transcription factor, required for downstream transcriptional signaling following binding to proteins in the PAS-B family. ARNT is the obligate dimer partner for HIF-1⍺, HIF-2⍺ and the aryl hydrocarbon receptor (AhR), indicating that this protein represents a key central node in the VHL/HIF/VEGF tumor signaling pathway. By targeting ARNT with a molecular glue degrader, downstream transcriptional activity can be inhibited. Therefore, the clinically validated pharmacology observed with HIF-2⍺ blockade can be captured, along with the additional activities conveyed by blocking the activity of HIF-1⍺ and AhR. ARNT was identified as a molecular glue degradation target of the CRL4CRBN E3 ligase through profiling of a chemically diverse compound library. ARNT is not degraded by clinically approved cereblon-dependent IMiD drugs and had not been reported to be a degradable neosubstrate or to contain known ‘degron’ features. ARNT was subsequently validated as a direct novel degradation neosusbtrate using biochemical assays and high resolution cryoEM structural studies. Structural analysis revealed that ARNT engages cereblon through a multi-domain interface formed via a large conformational change. High resolution structures guided iterative structure-based drug design throughout the program, enabling rapid medicinal chemistry optimization. Here we present the discovery of NEO-811, a potent, selective, and cereblon-dependent molecular glue degrader of ARNT. NEO-811 degrades ARNT with nanomolar potency in vitro, potently inhibiting downstream VEGF transcription. NEO-811 does not degrade the classical cereblon neosubstrates such as SALL4, IKZF1/3, or GSPT1, and does not exhibit cellular toxicity in vitro. In vivo studies show potent single agent anti-tumor effects in ccRCC xenograft models, leading to single agent tumor regression without exhibiting significant changes in body weight. NEO-811 also retains anti-tumor activity in a xenograft model carrying the HIF-2⍺ G323E mutation, a mutation identified in preclinical models and in ccRCC patients, that confers resistance to HIF-2⍺ antagonists. Additionally, PDX studies indicate that ARNT degradation can provide superior anti-tumor activity when compared to clinical HIF-2 antagonists and VEGFR tyrosine kinase inhibitors (TKIs). NEO-811 is currently in clinical development in the USA and Canada in a FIH Phase 1/2 study (Clinicaltrials. gov NCT07300241). This study will evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of NEO-811 administered as a single agent in adult subjects with locally advanced or metastatic non-resectable ccRCC. Citation Format: Jennifer Griffin, J. Scott Lee, Jake Fathman, Andres Hernandez, Xiaoxi Liu, Kurt Januszyk, Bryan Lee, Anthony Burt, John Tellew, Michelle Cruz, Isabella Tran, Kevin Chiu, Mengyu Wu, Leslie Bateman, Ana Dominguez-Andres, Ling Huang, Celin Sanchez, Nathalia Cruz, Zac Naiman, Randy Soriano, Devin Knece, Molly Fitzgibbon, Kiyoyuki Omoto, Kalistyn Burley, Brian Bear, Suzana Couto, Klaus Wagner, Ana Grant, Mary Matyskiela, Ben Wen, Rohan Beckwith, Philip Chamberlain. Development of NEO-811, a molecular glue degrader of ARNT (HIF-1β) with potent single agent activity in ccRCC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr ND01.