Abstract 6734: Discovery and optimization of NEO-811, a first-in-class molecular glue degrader of ARNT, utilizing structure-based drug design.

Abstract ARNT (HIF-1β), a member of the HIF family of transcription factors, heterodimerizes with HIF-2α to regulate the transcription of the hypoxic-response pathway. pVHL mutation leads to constitutive overactivation of HIF transcription, driving cancers such as clear cell renal cell carcinoma (ccRCC). Targeted degradation of ARNT represents a novel therapeutic approach to targeting this oncogenic pathway. Herein we disclose a structure-based drug design approach which afforded NEO-811, a first-in-class ARNT molecular glue degrader. Biochemical and cellular mechanism of action studies revealed ARNT degradation mediated by the CRL4-CRBN E3 ligase. A cryo-EM structure confirmed direct ARNT recruitment to CRBN and revealed opportunities to enhance the depth of degradation and selectivity against neosubstrates. A medicinal chemistry campaign incorporating structure-based drug design enabled the development of NEO-811, a potent and selective degrader of ARNT entering clinical trials for treatment of ccRCC. Citation Format: Jennifer Griffin, Andres Hernandez, Xiaoxi Liu, Kurt Januszyk, Bryan Lee, Anthony Burt, John Tellew, J. Scott Lee, Michelle Cruz, Isabella Tran, Kevin Chiu, Mengyu Wu, Leslie Bateman, Ana Dominguez-Andres, Ling Huang, Jake Fathman, Celin Sanchez, Nathalia Cruz, Randy Soriano, Devin Knece, Molly Fitzgibbon, Ana Grant, Mary Matyskiela, Rohan Beckwith, Phil Chamberlain, . Discovery and optimization of NEO-811, a first-in-class molecular glue degrader of ARNT, utilizing structure-based drug design [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 6734.