TY - JOUR
T1 - The androgen receptor in prostate cancer
T2 - Effect of structure, ligands and spliced variants on therapy
AU - Messner, Elisabeth A.
AU - Steele, Thomas M.
AU - Tsamouri, Maria Malvina
AU - Hejazi, Nazila
AU - Gao, Allen C.
AU - Mudryj, Maria
AU - Ghosh, Paramita M.
N1 - Funding Information:
Funding: This research received funding from the Department of Veterans Affairs, Merit Awards BX004423 (P.M.G.) and BX003458 (M.M.) and the National Institutes of Health R01CA185509 (P.M.G.).
PY - 2020/10
Y1 - 2020/10
N2 - The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand binding at the LBD promotes AR dimerization and translocation to the nucleus where the DBD binds target DNA. In PCa, AR signaling is perturbed by excessive androgen synthesis, AR amplification, mutation, or the formation of AR alternatively spliced variants (AR-V) that lack the LBD. Current therapies for advanced PCa include androgen synthesis inhibitors that suppress T and/or DHT synthesis, and AR inhibitors that prevent ligand binding at the LBD. However, AR mutations and AR-Vs render LBD-specific therapeutics ineffective. The DBD and NTD are novel targets for inhibition as both perform necessary roles in AR transcriptional activity and are less susceptible to AR alternative splicing compared to the LBD. DBD and NTD inhibition can potentially extend patient survival, improve quality of life, and overcome predominant mechanisms of resistance to current therapies. This review discusses various small molecule and other inhibitors developed against the DBD and NTD—and the current state of the available compounds in clinical development.
AB - The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand binding at the LBD promotes AR dimerization and translocation to the nucleus where the DBD binds target DNA. In PCa, AR signaling is perturbed by excessive androgen synthesis, AR amplification, mutation, or the formation of AR alternatively spliced variants (AR-V) that lack the LBD. Current therapies for advanced PCa include androgen synthesis inhibitors that suppress T and/or DHT synthesis, and AR inhibitors that prevent ligand binding at the LBD. However, AR mutations and AR-Vs render LBD-specific therapeutics ineffective. The DBD and NTD are novel targets for inhibition as both perform necessary roles in AR transcriptional activity and are less susceptible to AR alternative splicing compared to the LBD. DBD and NTD inhibition can potentially extend patient survival, improve quality of life, and overcome predominant mechanisms of resistance to current therapies. This review discusses various small molecule and other inhibitors developed against the DBD and NTD—and the current state of the available compounds in clinical development.
KW - Alternatively spliced variants
KW - Androgen receptor
KW - Castration-resistant prostate cancer
KW - DNA-binding domain
KW - Ligand-binding domain
KW - N-terminal domain
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U2 - 10.3390/biomedicines8100422
DO - 10.3390/biomedicines8100422
M3 - Review article
AN - SCOPUS:85093970608
VL - 8
SP - 1
EP - 19
JO - Biomedicines
JF - Biomedicines
SN - 2227-9059
IS - 10
M1 - 422
ER -