Abstract 5601: ID11916, a novel androgen receptor antagonist with cGMP-dependent protein kinase activation for next-generation therapeutics in AR positive tumors

Abstract Androgen receptor (AR) signaling plays a crucial role in hormone-dependent cancers. In prostate cancer, AR signaling-targeted therapies, including second-generation AR antagonists such as enzalutamide, are initially effective for castration-resistant prostate cancer, but often develop resistance. AR is expressed in 60-80% of breast cancers and known to contribute to tumor aggressiveness. However, the clinical efficacy of AR-targeted therapies in breast cancer remains limited. Therefore, numerous AR targeted therapies are under development to improve efficacy and overcome resistance. However, given that AR resistance results from the complex interplay of both AR-dependent and AR-independent mechanisms, a strategy targeting both pathways is required. We developed ID11916, a novel orally available AR antagonist that modulates AR-dependent and AR-independent pathways by activating cGMP-dependent protein kinase (PKG). ID11916 effectively blocks androgen binding to AR, nuclear translocation, and androgen-dependent transcriptional activity of AR, while increasing intracellular cGMP levels and activating PKG via phosphodiesterase 5 inhibition. ID11916 demonstrated potent anti-cancer effect in prostate cancer cell lines VCaP and 22Rv1, where enzalutamide showed limited efficacy. In VCaP, where bicalutamide exhibited an agonistic effect, ID11916 showed approximately 60-fold greater anti-proliferative activity (IC50: 2.77 μM) than enzalutamide (IC50: 163 μM). ID11916 demonstrated greater potency in colony formation assays than enzalutamide in AR-positive breast cancer cell lines SK-BR-3 (ID11916 IC50: 0.653 μM vs Enzalutamide IC50: > 30.0 μM) and MDA-MB-231 (ID11916 IC50: 1.96 μM vs Enzalutamide IC50: 18.1 μM). ID11916 also showed superior tumor growth inhibition in xenograft models. In the MDA-MB-453 xenograft model, daily oral administration of ID11916 at 30 mg/kg inhibited tumor growth by 74.7%, compared to 53.0% inhibition with clinically relevant dose of enzalutamide. In a repeated-dose pharmacokinetic study in the MDA-MB-453 xenograft model, oral administration of 30 mg/kg ID11916 showed a 7-fold lower Cmax and an 8-fold lower AUC compared to enzalutamide. These findings indicate that the enhanced potency of ID11916 compared to enzalutamide is consistently demonstrated in vivo. In conclusion, our preclinical data introduce ID11916, a novel compound with a potential of overcoming resistance through both AR-dependent and AR-independent mechanisms by combining AR and PKG modulation. These findings support its potential as a next-generation AR-targeted therapy, offering an alternative to currently available AR targeting approaches. Citation Format: Jeong Eun Kim, Ji-Yun Lee, Jaebeom Cho, Won Sik Lee, Myongjae Lee. ID11916, a novel androgen receptor antagonist with cGMP-dependent protein kinase activation for next-generation therapeutics in AR positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5601.