Abstract B096: Targeting NONO as a therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC)
Metastatic castration-resistant prostate cancer (mCRPC) remains driven by persistent androgen receptor (AR) signaling, including ligand-independent activity mediated by AR splice variants such as AR-V7. These variants are not addressed by current therapies, highlighting the need for novel approaches to suppress AR signaling.Here, we describe a first-in-class strategy targeting the RNA-binding protein NONO using TF-Scan, a mass spectrometry–based functional proteomics platform that quantifies chromatin-associated protein networks in live cells. NONO is involved in the alternative splicing of a subset of mRNAs, including AR, enabling a unique opportunity to target all AR isoforms, including mutants and splice variants.Using TF-Scan, we identified a covalent small-molecule series that selectively engages NONO at C145 in prostate cancer cells. Mechanistically, these compounds act as RNA molecular glues, modulating the association of NONO to AR pre-mRNA and altering its processing. This results in reduced accumulation of AR mRNA isoforms and decreased levels of both full-length AR and AR-V7 proteins.TF-Scan profiling demonstrates a concomitant reduction in chromatin-bound AR and HOXB13, confirming pathway suppression at the functional level. Through iterative medicinal chemistry guided by proteome-wide selectivity and functional readouts, we optimized compounds with sub-micromolar potency and robust anti-proliferative activity in AR-dependent models. Importantly, using an inactive enantiomer and RNA-seq, we demonstrate that our compounds are highly selective, perturbing a restricted subset of genes, including AR.Together, these findings establish NONO as a tractable target in mCRPC and introduce RNA molecular gluing as a novel modality to suppress AR signaling. More broadly, this work highlights the power of mass spectrometry–based functional proteomics to enable drug discovery against transcriptional regulators and RNA-processing proteins. Brian McEllin, Daniele Canzani, Lindsay Pino, David Moebius, Gaelle Mercenne, Alexander Federation. Targeting NONO as a therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B096.