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Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors by Zachary T.K. Gannam; Haya Jamali; Oh Sang Kweon; James Herrington; Shanelle R. Shillingford; Christina Papini; Erik Gentzel; Elias Lolis; Anton M. Bennett; Jonathan A. Ellman; Karen S. Anderson is a Chemistry article available to read on EtoBox.
What is Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors about?
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 thi
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- Author
- Zachary T.K. Gannam; Haya Jamali; Oh Sang Kweon; James Herrington; Shanelle R. Shillingford; Christina Papini; Erik Gentzel; Elias Lolis; Anton M. Bennett; Jonathan A. Ellman; Karen S. Anderson
- Publisher
- Elsevier BV
- Published
- 2022
- Language
- EN
- Field
- Chemistry (Physical Sciences)