Degradation of all forms of androgen receptors (ARs) is emerging as an advantageous therapeutic paradigm for the effective treatment of prostate cancer. In continuation of our program to identify and develop improved efficacious novel small-molecule agents designed to disrupt AR signaling through enhanced AR degradation, we have designed, synthesized, and evaluated novel C-3 modified analogues of our phase 3 clinical agent, galeterone (5). Concerns of potential in vivo stability of our recently discovered more efficacious galeterone 3β-imidazole carbamate (6) led to the design and synthesis of new steroidal compounds. Two of the 11 compounds, 3β-pyridyl ether (8) and 3β-imidazole (17) with antiproliferative GI50 values of 3.24 and 2.54 μM against CWR22Rv1 prostate cancer cell, are 2.75- and 3.5-fold superior to 5. In addition, compounds 8 and 17 possess improved (∼4-fold) AR-V7 degrading activities. Importantly, these two compounds are expected to be metabolically stable, making them suitable for further development as new therapeutics against all forms of prostate cancer.
ACS medicinal chemistry letters. 2016 May 23*** epublish ***
Puranik Purushottamachar, Andrew K Kwegyir-Afful, Marlena S Martin, Vidya P Ramamurthy, Senthilmurugan Ramalingam, Vincent C O Njar
Department of Pharmacology, Center for Biomolecular Therapeutics, and Marlene Stewart Greenbaum Cancer Center, University of Maryland School of Medicine , 685 West Baltimore Street, Baltimore, Maryland 21201-1559, United States., Department of Pharmacology, Center for Biomolecular Therapeutics, and Marlene Stewart Greenbaum Cancer Center, University of Maryland School of Medicine , 685 West Baltimore Street, Baltimore, Maryland 21201-1559, United States., Department of Pharmacology, Center for Biomolecular Therapeutics, and Marlene Stewart Greenbaum Cancer Center, University of Maryland School of Medicine , 685 West Baltimore Street, Baltimore, Maryland 21201-1559, United States., Department of Pharmacology, Center for Biomolecular Therapeutics, and Marlene Stewart Greenbaum Cancer Center, University of Maryland School of Medicine , 685 West Baltimore Street, Baltimore, Maryland 21201-1559, United States., Department of Pharmacology, Center for Biomolecular Therapeutics, and Marlene Stewart Greenbaum Cancer Center, University of Maryland School of Medicine , 685 West Baltimore Street, Baltimore, Maryland 21201-1559, United States., Department of Pharmacology, Center for Biomolecular Therapeutics, and Marlene Stewart Greenbaum Cancer Center, University of Maryland School of Medicine , 685 West Baltimore Street, Baltimore, Maryland 21201-1559, United States.