دورية أكاديمية
Discovery and characterization of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists.
| العنوان: | Discovery and characterization of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists. |
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| المؤلفون: | Orsi DL; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Ferrara SJ; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Siegel S; Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany., Friberg A; Nuvisan ICB GmbH, 13353 Berlin, Germany., Bouché L; Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany., Pook E; Research and Development, Pharmaceuticals, Bayer AG, 42113 Wuppertal, Germany., Lienau P; Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany., Bluck JP; Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany., Lemke CT; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Akcay G; Bayer US LLC, Research and Development Precision Molecular Oncology, Cambridge, MA 02142, USA., Stellfeld T; Nuvisan ICB GmbH, 13353 Berlin, Germany., Meyer H; Nuvisan ICB GmbH, 13353 Berlin, Germany., Pütter V; Nuvisan ICB GmbH, 13353 Berlin, Germany., Holton SJ; Nuvisan ICB GmbH, 13353 Berlin, Germany., Korr D; Nuvisan ICB GmbH, 13353 Berlin, Germany., Jerchel-Furau I; Bayer US LLC, Research and Development Precision Molecular Oncology, Cambridge, MA 02142, USA., Pantelidou C; Bayer US LLC, Research and Development Precision Molecular Oncology, Cambridge, MA 02142, USA., Strathdee CA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Meyerson M; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics and Medicine, Harvard Medical School, Boston, MA 02115, USA., Eis K; Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany., Goldstein JT; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: jgold@broadinstitute.org. |
| المصدر: | Bioorganic & medicinal chemistry [Bioorg Med Chem] 2023 Jan 15; Vol. 78, pp. 117130. Date of Electronic Publication: 2022 Dec 13. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Elsevier Science Original Publication: Oxford : New York : Pergamon Press, c1993- |
| مواضيع طبية MeSH: | PPAR gamma*/agonists , Urinary Bladder Neoplasms*, Humans ; Drug Inverse Agonism ; PPAR-gamma Agonists ; Gene Expression Regulation |
| مستخلص: | PPAR gamma (PPARG) is a ligand activated transcription factor that regulates genes involved in inflammation, bone biology, lipid homeostasis, as well as a master regulator of adipogenesis and a potential lineage driver of luminal bladder cancer. While PPARG agonists lead to transcriptional activation of canonical target genes, inverse agonists have the opposite effect through inducing a transcriptionally repressive complex leading to repression of canonical target gene expression. While many agonists have been described and tested clinically, inverse agonists offer an underexplored avenue to modulate PPARG biology in vivo. Current inverse agonists lack favorable in vivo properties; herein we describe the discovery and characterization of a series of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists, BAY-5516, BAY-5094, and BAY-9683. Structural studies of this series revealed distinct pre- and post-covalent binding positions, which led to the hypothesis that interactions in the pre-covalent conformation are primarily responsible for driving affinity, while interactions in the post-covalent conformation are more responsible for cellular functional effects by enhancing PPARG interactions with its corepressors. The need to simultaneously optimize for two distinct states may partially explain the steep SAR observed. Exquisite selectivity was achieved over related nuclear receptors in the subfamily due in part to a covalent warhead with low reactivity through an S Competing Interests: 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. (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.) |
| معلومات مُعتمدة: | R35 CA197568 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: Inverse-agonist; Nuclear receptor; PPARG; Peroxisome proliferator-activated receptor |
| المشرفين على المادة: | 0 (PPAR gamma) 0 (PPAR-gamma Agonists) |
| تواريخ الأحداث: | Date Created: 20221221 Date Completed: 20230117 Latest Revision: 20230428 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.bmc.2022.117130 |
| PMID: | 36542958 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1464-3391 |
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| DOI: | 10.1016/j.bmc.2022.117130 |