An oral androgen receptor RIPTAC for prostate cancer.

184 Background: Resistance to Androgen Receptor Signaling Inhibitors (ARSIs) in prostate cancer occurs in almost all patients and is driven primarily by genomic alterations in AR and increases in AR expression. In the metastatic castration-resistant setting, more than 80% of these patients harbor amplifications of the AR gene or the upstream enhancer region of DNA. Our RIPTAC technology leverages the high level of AR expression to selectively kill prostate cancer cells while sparing normal tissues. Methods: We describe here a novel orally bioavailable heterobifunctional small molecule AR RIPTAC that recruits an essential cellular protein (EP) into a stable ternary complex with AR, thereby inhibiting EP function and leading to cell death selectively in AR-positive cells. Molecules were designed to achieve cooperative binding between AR and EP, oral bioavailability and AR-selective cell killing. Results: AR RIPTACs form a ternary complex between AR and EP across PCa cell lines with an EC 50 ~1nM, leading to concomitant inhibition of the EP and antiproliferative activity across PCa cell lines. The cell killing activity of AR RIPTACs is dependent on the presence of AR in the cell. AR RIPTACs induce apoptosis at low nM concentrations in cells overexpressing AR but not in control cells. In castrated mice bearing VCaP xenografts, AR RIPTACs accumulate in the tumor and induce AR:RIPTAC:EP ternary complex formation at a low oral dose, resulting in tumor specific inhibition of the EP and tumor growth inhibition. Leading AR RIPTACs possess pharmacokinetic properties suitable for a drug candidate, and readily achieve efficacious exposures following oral dosing in mouse, rat and dog. Conclusions: In summary, we report preclinical data on orally bioavailable heterobifunctional AR RIPTACs that are active in multiple prostate cancer models. The lead molecules are being evaluated in toxicology studies, with IND filing slated for 2024.