دورية أكاديمية
أعرض في EDS

Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.

التفاصيل البيبلوغرافية
العنوان: Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.
المؤلفون: Gustafson JL; Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA)., Neklesa TK; Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA)., Cox CS; Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA)., Roth AG; Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA)., Buckley DL; Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA)., Tae HS; Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA)., Sundberg TB; Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA)., Stagg DB; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 (USA)., Hines J; Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA)., McDonnell DP; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 (USA)., Norris JD; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 (USA)., Crews CM; Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA). craig.crews@yale.edu.
المصدر: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2015 Aug 10; Vol. 54 (33), pp. 9659-62. Date of Electronic Publication: 2015 Jun 17.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 0370543 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-3773 (Electronic) Linking ISSN: 14337851 NLM ISO Abbreviation: Angew Chem Int Ed Engl Subsets: MEDLINE
أسماء مطبوعة: Publication: <2004-> : Weinheim : Wiley-VCH
Original Publication: Weinheim/Bergstr. : New York, : Verlag Chemie ; Academic Press, c1962-
مواضيع طبية MeSH: Androgen Receptor Antagonists/*chemistry , Androgen Receptor Antagonists/*pharmacology , Proteolysis/*drug effects , Receptors, Androgen/*metabolism , Small Molecule Libraries/*chemistry , Small Molecule Libraries/*pharmacology, Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Benzamides ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm ; Humans ; Hydrophobic and Hydrophilic Interactions ; Male ; Nitriles ; Phenylthiohydantoin/analogs & derivatives ; Phenylthiohydantoin/chemistry ; Phenylthiohydantoin/pharmacology ; Point Mutation ; Prostate/drug effects ; Prostate/metabolism ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Receptors, Androgen/genetics
مستخلص: Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of selective androgen receptor degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small-molecule AR ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to second-generation AR antagonists.
(© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
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معلومات مُعتمدة: R01 CA139818 United States CA NCI NIH HHS; R01CA139818 United States CA NCI NIH HHS; T32 GM067543 United States GM NIGMS NIH HHS; R01 AI084140 United States AI NIAID NIH HHS; F32GM10052101 United States GM NIGMS NIH HHS; R01AI084140 United States AI NIAID NIH HHS; F32 GM100521 United States GM NIGMS NIH HHS; T32GM067543 United States GM NIGMS NIH HHS
فهرسة مساهمة: Keywords: antiproliferation; cancer; drug design; hormones; protein degradation
المشرفين على المادة: 0 (AR protein, human)
0 (Androgen Receptor Antagonists)
0 (Antineoplastic Agents)
0 (Benzamides)
0 (Nitriles)
0 (Receptors, Androgen)
0 (Small Molecule Libraries)
2010-15-3 (Phenylthiohydantoin)
93T0T9GKNU (enzalutamide)
تواريخ الأحداث: Date Created: 20150618 Date Completed: 20160517 Latest Revision: 20240518
رمز التحديث: 20240518
مُعرف محوري في PubMed: PMC4547777
DOI: 10.1002/anie.201503720
PMID: 26083457
قاعدة البيانات: MEDLINE
الوصف
تدمد:1521-3773
DOI:10.1002/anie.201503720