Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors.

Autor: Gannam ZTK; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA., Jamali H; Department of Chemistry, Yale University School of Medicine, New Haven, CT, 06520, USA., Kweon OS; Department of Chemistry, Yale University School of Medicine, New Haven, CT, 06520, USA., Herrington J; Yale Center for Molecular Discovery, Yale University School of Medicine, New Haven, CT, 06520, USA., Shillingford SR; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA., Papini C; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA., Gentzel E; Department of Chemistry, Yale University School of Medicine, New Haven, CT, 06520, USA., Lolis E; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA. Electronic address: elias.lolis@yale.edu., Bennett AM; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA; Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA. Electronic address: anton.bennett@yale.edu., Ellman JA; Department of Chemistry, Yale University School of Medicine, New Haven, CT, 06520, USA. Electronic address: jonathan.ellman@yale.edu., Anderson KS; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, 06520, USA. Electronic address: karen.anderson@yale.edu.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2022 Dec 05; Vol. 243, pp. 114712. Date of Electronic Publication: 2022 Sep 02.
DOI: 10.1016/j.ejmech.2022.114712
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anton Bennett, Jonathan Ellman, Elias Lolis, Haya Jamali, Karen Anderson has patent #US2018/066191 pending to Yale University.
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Databáze: MEDLINE
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