Abstract LB007: Discovery of a novel molecular glue degrader of Nrf2

Abstract Nrf2 is an oncogenic transcription factor that is frequently overactive in tumors bearing mutations in the NRF2/KEAP1 pathway, but to date, no direct Nrf2 inhibitors have been tested clinically. Using high-throughput transcriptomic screens in combination with biophysical assays, we discovered ARP-4922 as a potent molecular glue degrader of Nrf2. ARP-4922 degrades Nrf2 in a proteasome- and cullin- dependent manner with exceptional activity, especially in NRF2/KEAP1-mutant backgrounds. Genetic experiments identified the likely E3 ligase driving ARP-4922-mediated degradation of Nrf2, and biophysical approaches such as fluorescence polarization (FP) and size exclusion chromatography followed by affinity selection mass spectrometry (SEC-ASMS) confirmed the E3 ligase required for ARP-4922-mediated ternary complex formation and subsequent Nrf2 degradation. Importantly, FP experiments allowed definition of the E3 ligase-interacting degron within the Nrf2 protein and can distinguish between active and inactive ARP-4922 analogs. ARP-4922 has a favorable in vivo pharmacokinetic profile in mice and leads to 100% tumor growth inhibition in several cell-derived xenograft models, including models of lung adenocarcinoma (NCI-H2122) and lung squamous cell carcinoma (LK2), which possess mutations in KEAP1 and NRF2 respectively. ARP-4922 represents a promising novel approach to Nrf2 inhibition in NRF2/KEAP1 mutant cancers with high unmet medical need. Citation Format: Timothy J. Read, Richard Steel, Leah Damon, Reo Yoo, Ardeshir Goliaei, Jenna Rimel, Jeff Hsu, David Simpson, Joseph Azofeifa. Discovery of a novel molecular glue degrader of Nrf2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB007.