Discovery of thiohydantoin based antagonists of androgen receptor with efficient degradation for the treatment of prostate cancer.

Male Humans Receptors, Androgen / metabolism Thiohydantoins / chemistry Prostatic Neoplasms / drug therapy Androgen Receptor Antagonists / chemistry Cell Line, Tumor Androgen Antagonists / pharmacology Cell Proliferation
Androgen receptor Antagonist Degradation Prostate cancer

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
05 Sep 2023
Historique:
received: 14 03 2023
revised: 12 05 2023
accepted: 14 05 2023
medline: 19 6 2023
pubmed: 21 5 2023
entrez: 20 5 2023
Statut: ppublish

Résumé

Prostate cancer (PC) is one of the most prevalent cancers in men worldwide, and androgen receptor (AR) is a well-validated drug target for the treatment of PC. However, PC often exhibits resistance to AR antagonists over time. Thus, it is urgent to identify novel and effective drugs for PC treatment. A series of novel thiohydantoin based AR antagonists with efficient degradation against AR were designed, synthesized, and evaluated. Based on our previous SAR and further structural optimization, a tool molecule 26h was discovered with dual mechanisms including improved antagonistic activity and potent degradation (AR-fl and AR-V7). Moreover, 26h can also effectively block AR nuclear translocation and inhibit AR/AR-V7 heterodimerization, thereby inhibiting downstream gene transcription. Importantly, 26h displayed potent robust efficacy in LNCaP (TGI: 70.70%) and 22Rv1 (TGI: 78.89%) xenograft models. This provides new design strategies and advantageous potential compounds for the treatment of prostate cancer.

Identifiants

DOI: 10.1016/j.ejmech.2023.115490 PMID: 37209451
pubmed: 37209451
pii: S0223-5234(23)00456-7
doi: 10.1016/j.ejmech.2023.115490
pii:
doi:

Substances chimiques

Receptors, Androgen 0
Thiohydantoins 0
Androgen Receptor Antagonists 0
Androgen Antagonists 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

115490

Informations de copyright

Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Xiujin Chang (X)

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.

Di Zhang (D)

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.

Fangui Qu (F)

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.

Youquan Xie (Y)

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.

Tian Chen (T)

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.

Yuqing Zhang (Y)

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.

Qianming Du (Q)

General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.

Jinlei Bian (J)

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.

Zhiyu Li (Z)

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.

Jubo Wang (J)

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: 1620194588@cpu.edu.cn.

Xi Xu (X)

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: xuxi@cpu.edu.cn.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Discovery of thiohydantoin based antagonists...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteurs aux androgènes › Discovery of thiohydantoin based antagonists...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Imidazoles › Imidazolidines › Hydantoïnes › Thiohydantoïnes › Discovery of thiohydantoin based antagonists...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Discovery of thiohydantoin based antagonists...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hormones, substituts d'hormones et antagonistes d'hormones › Antihormones › Antagonistes des androgènes › Antagonistes du récepteur des androgènes › Discovery of thiohydantoin based antagonists...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Discovery of thiohydantoin based antagonists...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hormones, substituts d'hormones et antagonistes d'hormones › Antihormones › Antagonistes des androgènes › Discovery of thiohydantoin based antagonists...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Discovery of thiohydantoin based antagonists...