发现FX-111：一种同类首创的转录活性雄激素受体（AR ON）异双功能降解剂，用于治疗AR驱动的前列腺癌患者

Significant unmet need exists in metastatic castration resistant prostate cancer (mCRPC). As the disease progresses, mutations, amplification and overexpression of the androgen receptor (AR), often accompanied by elevated intratumoral androgen levels, become increasingly prevalent, with 85% of mCRPC cases remaining AR-dependent. Current therapies target the cytoplasmic, hormone-unbound AR (AR OFF ); however, rising AR levels as prostate cancer (PC) advances represent a primary mechanism of resistance to these therapies. Nuclear, hormone-bound, transcriptionally active AR (AR ON ) is the main driver of androgen signaling and tumor progression in AR-dependent PC. Here we report the discovery of a selective AR ON degrader that utilizes a novel allosteric binding site revealed upon hormone binding. We identified multiple x-ray validated ligands that bind to this novel AR ON pocket. Conversion and optimization of these ligands into Cereblon-based heterobifunctional degraders resulted in the identification of FX-111. FX-111 achieves rapid and sustained degradation of AR (DC 50 = 10 nM) and displays exquisite selectivity, with no observed degradation of other steroid hormone receptors or other proteins using proteome-wide analysis in multiple cell lines. FX-111 degrades AR and silences AR target genes effectively irrespective of increasing hormone as it is non-competitive with androgen binding, in contrast to the loss of potency seen with orthosteric degraders with increasing hormone levels. FX-111 degrades AR ON when alternative agonists are used to stimulate its activity and can effectively degrade clinically relevant mutant forms of AR. RNA-seq analysis in LNCaP and VCaP cells treated with FX-111 reveals complete inhibition of androgen-driven transcriptional changes, with minimal gene expression impact in hormone-depleted conditions, underscoring FX-111's specificity for AR degradation. In vivo, FX-111 induces robust AR degradation, prostate specific antigen suppression and significant tumor growth inhibition in VCaP xenograft models, with oral administration at 10 mg/kg BID. Addition of exogenous androgen in intact or castrated mice, mimicking intratumoral hormone, did not affect the pharmacodynamic profile or efficacy of FX-111, whereas orthosteric degraders lost both potency and the ability to suppress AR transcriptional activity. Potent suppression of AR function in prostate and testes tissues, with accompanying organ weight loss, was observed in mice. Targeting AR ON in PC could potentially treat all forms of PC that are driven by AR signaling without the need for androgen deprivation. FX-111 is currently in IND-enabling studies with plans to initiate clinical studies in 2026.