Preclinical characterization of NEO-811, a novel molecular glue degrader of ARNT for the treatment of clear cell renal cell carcinoma
Presenter: J. Scott Lee, BA;PhD Session: Proximity-Induced Drug Discovery 2 Time: 4/21/2026 2:00:00 PM → 4/21/2026 5:00:00 PM
Authors
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 Neomorph, Inc, San Diego, CA
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.
Disclosure
J. Lee, Neomorph, Inc Employment, Stock Option. M. S. Cruz, Neomorph, Inc Employment, Stock Option. I. Tran, Neomorph, Inc Employment, Stock Option. K. Chiu, Neomorph, Inc Employment, Stock Option. J. Griffin, Neomorph, Inc Employment, Stock Option. A. de la Peña, Neomorph, Inc Employment, Stock Option. K. Januszyk, Neomorph, Inc Employment, Stock Option. X. Liu, Neomorph, Inc Employment, Stock Option. B. Lee, Neomorph, Inc Employment, Stock Option. A. Burt, Neomorph, Inc Employment, Stock Option. J. Tellew, Neomorph, Inc Employment, Stock Option. M. Wu, Neomorph, Inc Employment, Stock Option. L. Watson, Neomorph, Inc Employment, Stock Option. A. Dominguez-Andres, Neomorph, Inc Employment, Stock Option. L. Huang, Neomorph, Inc Employment, Stock Option. R. Soriano, Randy Soriano Employment, Stock Option. D. Knece, Neomorph, Inc Employment, Stock Option. M. FitzGibbon, Neomorph, Inc Employment, Stock Option. J. Fathman, Neomorph, Inc Employment, Stock Option. C. Sanchez, Neomorph, Inc Employment, Stock Option. N. Cruz, Neomorph, Inc Employment, Stock Option. Z. Neiman, Neomorph, Inc Employment, Stock Option. A. Grant, Neomorph, Inc Employment, Stock Option. M. Matyskiela, Neomorph, Inc Employment, Stock Option. R. Beckwith, Neomorph, Inc Employment, Stock Option. B. Wen, Neomorph, Inc Employment, Stock Option. K. Wagner, Neomorph, Inc Employment, Stock Option. P. Chamberlain, Neomorph, Inc Employment, Stock Option.
Cited in
Control: 7268 · Presentation Id: 8744 · Meeting 21436