Current treatment options for advanced castration-resistant prostate cancers (CRPC) are effective for a brief period before becoming refractory. It is important to use relevant in vivo models for candidate selection in the development of next-generation mechanistically-distinct drugs to treat castration- and drug- resistant prostate cancers. Here, we describe a series of AR pan-antagonists (selective AR degraders (SARDs)) that degrade the AR and AR splice variants. SARDs inhibit the wild-type and LBD mutant ARs comparably and inhibit the in vitro proliferation and in vivo growth of enzalutamide-sensitive and resistant prostate cancer xenografts. Xenograft studies conducted in immune-compromised SRG rats (Sprague Dawley Rag2-/- Il2rg -/-; Hera Biolabs) with three lead SARDs demonstrated regression of enzalutamide-sensitive and -resistant VCaP tumors both in castrated and in intact rats. SRG rats provide the benefit of abundant blood samples for weekly evaluation of rising PSA, which also indicated that the SARDs inhibit the rising PSA, while enzalutamide was inactive in enzalutamide-resistant model. Drug metabolism and pharmacokinetic (DMPK) studies, also conducted with SRG and wild-type rats and in combination with efficacy, indicate that the molecules possess all the necessary drug-like properties. The molecules exhibit a broad safety margin with no cross-reactivity with G-Protein Coupled Receptor, kinase, and nuclear receptor family members. Collectively, the SARDs exhibit the properties necessary for a next-generation prostate cancer drug and that use of SRG rats facilitated thorough characterization of their in vivo properties.

Citation Format: Suriyan Udhayasuriyan Ponnusamy, Fallon K Noto, Bisoye Towobola Adedeji, Yali He, Dong-Jin Hwang, Sam Moody, Thirumagal Thiyagarajan, Tseten Yeshi Jamling, Duane D Miller, Ramesh Narayanan. Potential next-generation androgen receptor-targeted therapeutic for enzalutamide-resistant prostate cancer; In vivo characterization in immune-compromised SRG rats [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B037. doi:10.1158/1535-7163.TARG-19-B037