2. Academic Validation
  3. Discovery by Virtual Screening of an Inhibitor of CDK5-Mediated PPARγ Phosphorylation

Discovery by Virtual Screening of an Inhibitor of CDK5-Mediated PPARγ Phosphorylation

  • ACS Med Chem Lett. 2022 Mar 11;13(4):681-686. doi: 10.1021/acsmedchemlett.1c00715.
Gavin O'Mahony 1,  Jens Petersen 2,  Margareta Ek 2,  Rebecca Rae 3,  Carina Johansson 2,  Liu Jianming 4,  Nina Prokoph 4,  Fredrik Bergström 5,  Krister Bamberg 6,  Fabrizio Giordanetto 1,  Bader Zarrouki 6,  Daniel Karlsson 6,  Anders Hogner 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden.
  • 2 Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden.
  • 3 Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden.
  • 4 Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden.
  • 5 DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden.
  • 6 Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden.
PMID: 35450368 DOI: 10.1021/acsmedchemlett.1c00715
Abstract

Thiazolidinedione PPARγ agonists such as rosiglitazone and pioglitazone are effective antidiabetic drugs, but side effects have limited their use. It has been posited that their positive antidiabetic effects are mainly mediated by the inhibition of the CDK5-mediated Ser273 phosphorylation of PPARγ, whereas the side effects are linked to classical PPARγ agonism. Thus compounds that inhibit PPARγ Ser273 phosphorylation but lack classical PPARγ agonism have been sought as safer antidiabetic therapies. Herein we report the discovery by virtual screening of 10, which is a potent PPARγ binder and in vitro inhibitor of the CDK5-mediated phosphorylation of PPARγ Ser273 and displays negligible PPARγ agonism in a reporter gene assay. The pharmacokinetic properties of 10 are compatible with oral dosing, enabling preclinical in vivo testing, and a 7 day treatment demonstrated an improvement in Insulin sensitivity in the ob/ob diabetic mouse model.

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