Abstract 5339: Paradoxical androgen receptor regulation by small molecule enantiomers

Small molecules that target the androgen receptor (AR) are the mainstay of therapy for lethal castration-resistant prostate cancer (CRPC), but they ultimately lead to resistance and progression to terminal disease. While individual resistance-associated AR mutations have been identified, the underlying mechanisms remain poorly understood. Here, we report a new class of AR-targeting compounds derived from the anti-androgen BMS-641988 (N-((3aR,4R,5R,7R,7aS)-2-(4-cyano-3-(trifluoromethyl)phenyl)-4,7-dimethyl-1,3-dioxooctahydro-1H-4,7-epoxyisoindol-5-yl)ethanesulfonamide) that reveal unexpected biological behavior: as expected, the C-5 (R)-enantiomers are antagonists, however the corresponding (S)-enantiomers, including the previously unknown C-5 (S)-enantiomer of BMS-641988 itself, are potent agonists of AR, with ED50 values comparable to dihydrotestosterone and R1881. A series of in vitro assays that interrogate different steps of AR functionality–including AR binding via fluorescence polarization, nuclear translocation and hyperspeckling via live cell confocal microscopy, ARE-luciferase, and RT qPCR arrays–confirm that the (R)-enantiomers are potent antagonists of AR in multiple cell lines, including AR T877A mutation-expressing LNCaP and AR overexpressing VCaP. While these cells are virtually resistant to BMS-641988, two of the novel derivatives, (R)-USC-1702 and (R)-USC-1707, inhibited their growth with IC50 values in the lower nM range. Importantly, these compounds do not produce the toxic metabolite that led to the clinical failure of BMS-641988. This is the first documented evidence of small molecule enantiomer pairs showing opposite functional effects while targeting AR. This new AR regulation duality augments our understanding of AR function and may have implications for anti-androgen drug development. Citation Format: Katherin Patsch, Chao Liu, Boris Kashemirov, Harish Sura, Grzegorz Zapotoczny, Yuanye Sun, Pavan P. Shah, Jonathan E. Katz, Sujatha Chilakala, Ah Young Joo, Nolan Ung, Maya Aljehani, Ren X. Sun, David B. Agus, Daniel Ruderman, Charles E. McKenna. Paradoxical androgen receptor regulation by small molecule enantiomers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5339.