靶向NONO作为转移性去势抵抗性前列腺癌(mCRPC)的治疗策略

Prostate cancer is among the most prevalent cancers among men, with approximately 300,000 new cases diagnosed annually. While androgen deprivation therapy (ADT) is effective in controlling early-stage prostate cancer, treatment options are limited once the disease advances to metastatic castration-resistant prostate cancer (mCRPC). This progression underscores the critical need for innovative therapeutic strategies to address this difficult-to-treat stage. Resistance to ADT arises when androgen receptor (AR) signaling becomes active even in the absence of ligands. This resistance is often driven by mutations in the ligand-binding domain (LBD) of AR or the expression of AR variants (AR-Vs) that lack the LBD. Uncovering new strategies to inhibit these constitutively active AR-Vs could provide significant clinical benefit for patients with mCRPC. Talus Bio has developed a groundbreaking technology, TF-Scan, the first cell-based global screening platform specifically designed to target transcription factors (TF) and other regulome proteins. TF-Scan integrates functional proteomics, automated cell processing, and machine learning to evaluate a drug's ability to modulate the activity of DNA-bound proteins in live human cells. This is an ideal system to identify and optimize compounds that suppress AR through direct or indirect mechanisms. Building on this mechanistic insight, we applied TF-Scan to systematically identify covalent modulators of NONO (non-POU domain-containing octamer-binding protein) that disrupt AR expression and protein binding. We then initiated an iterative hit-to-lead optimization campaign leveraging TF-Scan to optimize NONO binding, AR disruption and proteome-wide selectivity.. Our chemical series engages NONO at C145 with high selectivity in intact prostate cancer cells and produces a consistent reduction in chromatin-bound AR. Lead compounds suppress both full-length AR and AR-V7 protein levels, downregulate multiple downstream AR/AR-V target genes, and achieve sub-micromolar EC50 values for blocking the accumulation of AR mRNA isoforms. These effects translate into concordant anti-proliferative activity in AR-dependent prostate cancer models. Several advanced analogs exhibit improved solubility, enhanced microsomal stability, and overall favorable ADME/PK profiles. Based on these results, we are advancing our most promising candidates into proof-of-concept in vivo efficacy studies to evaluate their potential as first-in-class NONO/AR-targeting therapeutics for mCRPC.