7U4R

Structure of MAP kinase phosphatase 5 in complex with 3,3-dimethyl-1-((9-propyl-5,6-dihydrothieno[2,3-h]quinazolin-2-yl)thio)butan-2-one, an allosteric inhibitor

Summary for 7U4R

• Entry DOI: 10.2210/pdb7u4r/pdb
• Descriptor: Dual specificity protein phosphatase 10, 3,3-dimethyl-1-{[(9aM)-9-propyl-5,6-dihydrothieno[2,3-h]quinazolin-2-yl]sulfanyl}butan-2-one (2 entities in total)
• Functional Keywords: phosphatase, protein-tyrosine phosphatase, dual specificity phosphatase, phosphatase-inhibitor complex, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 106862.99

Authors

Gannam, Z.T.K.,Jamali, H.,Gentzel, E.,Lolis, E.,Anderson, K.S.,Ellman, J.A.,Bennett, A.M. (deposition date: 2022-02-28, release date: 2022-10-05, Last modification date: 2023-10-18)

Primary citation

Gannam, Z.T.K.,Jamali, H.,Kweon, O.S.,Herrington, J.,Shillingford, S.R.,Papini, C.,Gentzel, E.,Lolis, E.,Bennett, A.M.,Ellman, J.A.,Anderson, K.S.
Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors.
Eur.J.Med.Chem., 243:114712-114712, 2022

PubMed Abstract: Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP5) is responsible for regulating the activity of the stress-responsive MAPKs and has been put forth as a potential therapeutic target for a number of diseases, including dystrophic muscle disease a fatal rare disease which has neither a treatment nor cure. In previous work, we identified Compound 1 (3,3-dimethyl-1-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)butan-2-one) as the lead compound of a novel class of MKP5 inhibitors. In this work, we explore the structure-activity relationship for inhibition of MKP5 through modifications to the scaffold and functional groups present in 1. A series of derivative compounds was designed, synthesized, and evaluated for inhibition of MKP5. In addition, the X-ray crystal structures of six enzyme-inhibitor complexes were solved, further elucidating the necessary requirements for MKP5 inhibition. We found that the parallel-displaced π-π interaction between the inhibitor three-ring core and Tyr435 is critical for modulating potency, and that modifications to the core and functionalization at the C-9 position are essential for ensuring proper positioning of the core for this interaction. These results lay the foundation from which more potent MKP5 allosteric inhibitors can be developed for potential therapeutics towards the treatment of dystrophic muscle disease.

PubMed: 36116232
DOI: 10.1016/j.ejmech.2022.114712

Experimental method

X-RAY DIFFRACTION (3.14 Å)