NEO-811

NEO-811 is a selective and orally active ARNT (HIF-1β) molecular glue degrader. NEO-811 is mediated by CRL4-CRBN E3 ligase for ARNT degradation. NEO-811 can be used for the study of clear cell renal cell carcinoma (ccRCC) ^{[1] [2]}.

In Vitro, NEO-811 is highly selective and does 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 suppresses expression of target genes regulated by other Class I bHLH-PAS transcription factors, including HIF-1α and aryl hydrocarbon receptor (AHR). NEO-811 retaines activity in HIF-2α inhibitor-resistant cells that harbored previously described mutations^[2].

References:
[1]. Jennifer Griffin, et al. Abstract 6734: Discovery and optimization of NEO-811, a first-in-class molecular glue degrader of ARNT, utilizing structure-based drug design. Cancer Res (2026) 86 (7_Supplement): 6734.
[2]. J. Scott Lee, et al. Abstract 5791: Preclinical characterization of NEO-811, a novel molecular glue degrader of ARNT for the treatment of clear cell renal cell carcinoma. Cancer Res (2026) 86 (7_Supplement): 5791.