An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

Autor: Suriyan Ponnusamy, Duane D. Miller, Dong Jin Hwang, Ramesh Narayanan, Michael L. Mohler, Yali He, Arunima Sikdar
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
medicine.drug_class
Antiandrogens
Drug Evaluation
Preclinical
androgen receptor (AR)
Review
Antiandrogen
urologic and male genital diseases
Catalysis
Inorganic Chemistry
Androgen deprivation therapy
lcsh:Chemistry
03 medical and health sciences
Prostate cancer
0302 clinical medicine
non-canonical
Androgen Receptor Antagonists
Animals
Humans
Medicine
selective AR degraders (SARD)
Molecular Targeted Therapy
Physical and Theoretical Chemistry
Molecular Biology
lcsh:QH301-705.5
Spectroscopy
Chemical castration
business.industry
Organic Chemistry
Proteolysis targeting chimera
Prostatic Neoplasms
General Medicine
medicine.disease
prostate cancer
Computer Science Applications
Androgen receptor
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Receptors
Androgen
Estrogen
030220 oncology & carcinogenesis
castration-resistant prostate cancer (CRPC)
Proteolysis
Cancer research
business
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 2124, p 2124 (2021)
International Journal of Molecular Sciences
ISSN: 1661-6596
1422-0067
Popis: Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.
Databáze: OpenAIRE
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