BMS-641988 / BMS - LARVOL DELTA

Paradoxical androgen receptor regulation by small molecule enantiomers. (PubMed, Proc Natl Acad Sci U S A) - "The antiandrogen BMS-641988, which has (R)-chirality at C-5 encompasses a previously uncharacterized (S)-stereoisomer that is, surprisingly, a potent agonist of AR, as demonstrated by transcriptional assays supported by cell imaging studies...Coupled with in silico modeling studies, the results inform an AR model that explains the switch from potent antagonist to high-affinity agonist in terms of C-5 substituent steric interactions with helix 12 of the ligand binding site. They imply strategies to overcome AR drug resistance and demonstrate that insufficient enantiopurity in this class of AR antagonist can confound efforts to correlate structure with function."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

[VIRTUAL] Design, synthesis and evaluation of antagonists of human androgen receptor (ACS-Fall 2020) - "Second generation anti-androgens such as enzalutamide are commonly used to combat advanced prostate cancer, but they usually fail to prevent progression to terminal disease due to drug resistance. Additionally, our preclinical leads inhibited the growth of LNCaP prostate cancer cells expressing T877A mutant AR, contrary to BMS-641988Computational models and microsomal metabolism studies were used to evaluate the safety profiles of our compounds. Our lead compounds were predicted to have low blood-brain barrier permeability and were not metabolized to the toxic metabolite BMS-501949.In conclusion, we identified efficacious and safe lead compounds that are suitable for further preclinical development as the next generation of prostate cancer treatment."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

[VIRTUAL] Paradoxical androgen receptor regulation by small molecule enantiomers (AACR-II 2020) - "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...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."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR