2. Academic Validation
  3. Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069

Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069

  • J Med Chem. 2022 Nov 10;65(21):14843-14863. doi: 10.1021/acs.jmedchem.2c01379.
Douglas L Orsi 1,  Elisabeth Pook 2,  Nico Bräuer 3,  Anders Friberg 3,  Philip Lienau 2,  Christopher T Lemke 1,  Timo Stellfeld 3,  Ulf Brüggemeier 2,  Vera Pütter 3,  Hanna Meyer 3,  Maria Baco 4,  Stephanie Tang 4,  Andrew D Cherniack 4 5,  Lindsay Westlake 4,  Samantha A Bender 4,  Mustafa Kocak 4,  Craig A Strathdee 4,  Matthew Meyerson 4 5 6 7,  Knut Eis 2,  Jonathan T Goldstein 4
Affiliations

Affiliations

  • 1 Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
  • 2 Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany.
  • 3 Nuvisan ICB GmbH, 13353 Berlin, Germany.
  • 4 Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 6 Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 7 Department of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States.
PMID: 36270630 DOI: 10.1021/acs.jmedchem.2c01379
Abstract

The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARG or PPARγ) represents a potential target for a new generation of Cancer therapeutics, especially in muscle-invasive luminal bladder Cancer where PPARγ is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPARγ that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. In vitro treatment of sensitive cell lines with these compounds results in the robust regulation of PPARγ target genes and antiproliferative effects. Despite their imperfect physicochemical properties, the compounds showed modest pharmacodynamic target regulation in vivo. Improvements to the in vitro potency and efficacy of BAY-4931 and BAY-0069 compared to those of previously described PPARγ inverse-agonists show that these compounds are novel tools for probing the in vitro biology of PPARγ inverse-agonism.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-148352
    98.83%, PPARγ Inverse-Agonist
  • HY-148351
    98.07%, PPARγ Inverse Agonist