title: Identification of Novel Steroidal Androgen Receptor Degrading Agents Inspired by Galeterone 3β-Imidazole Carbamate.
abstract: 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.
authors.affiliation: 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.
authors.forename: Puranik
authors.initials: P
authors.lastname: Purushottamachar
authors.affiliation: 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.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Kwegyir-Afful
authors.affiliation: 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.
authors.forename: Marlena S
authors.initials: MS
authors.lastname: Martin
authors.affiliation: 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.
authors.forename: Vidya P
authors.initials: VP
authors.lastname: Ramamurthy
authors.affiliation: 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.
authors.forename: Senthilmurugan
authors.initials: S
authors.lastname: Ramalingam
authors.affiliation: 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.
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
keywords: Androgen receptor (AR); androgen receptor degrading agents (ARDAs); prostate cancer; splice variant AR (AR-V7)