7QB1

PPARg in complex with inhibitor

This is a non-PDB format compatible entry.

Summary for 7QB1

• Entry DOI: 10.2210/pdb7qb1/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 3-[(3,4-dichlorophenyl)methyl]-4-oxidanylidene-6-phenoxy-phthalazine-1-carboxylic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: nuclear hormone receptor cdk9, nuclear protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 66462.30

Authors

Petersen, J. (deposition date: 2021-11-17, release date: 2022-05-04, Last modification date: 2024-05-01)

Primary citation

O'Mahony, G.,Petersen, J.,Ek, M.,Rae, R.,Johansson, C.,Jianming, L.,Prokoph, N.,Bergstrom, F.,Bamberg, K.,Giordanetto, F.,Zarrouki, B.,Karlsson, D.,Hogner, A.
Discovery by Virtual Screening of an Inhibitor of CDK5-Mediated PPAR gamma Phosphorylation.
Acs Med.Chem.Lett., 13:681-686, 2022

PubMed 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 , 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 are compatible with oral dosing, enabling preclinical in vivo testing, and a 7 day treatment demonstrated an improvement in insulin sensitivity in the diabetic mouse model.

PubMed: 35450368
DOI: 10.1021/acsmedchemlett.1c00715

Experimental method

X-RAY DIFFRACTION (2.2 Å)