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Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor.

Publication ,  Journal Article
Carlson, DA; Franke, AS; Weitzel, DH; Speer, BL; Hughes, PF; Hagerty, L; Fortner, CN; Veal, JM; Barta, TE; Zieba, BJ; Somlyo, AV; Deng, JT ...
Published in: ACS Chem Biol
December 20, 2013

DAPK1 and ZIPK (also called DAPK3) are closely related serine/threonine protein kinases that regulate programmed cell death and phosphorylation of non-muscle and smooth muscle myosin. We have developed a fluorescence linked enzyme chemoproteomic strategy (FLECS) for the rapid identification of inhibitors for any element of the purinome and identified a selective pyrazolo[3,4-d]pyrimidinone (HS38) that inhibits DAPK1 and ZIPK in an ATP-competitive manner at nanomolar concentrations. In cellular studies, HS38 decreased RLC20 phosphorylation. In ex vivo studies, HS38 decreased contractile force generated in mouse aorta, rabbit ileum, and calyculin A stimulated arterial muscle by decreasing RLC20 and MYPT1 phosphorylation. The inhibitor also promoted relaxation in Ca(2+)-sensitized vessels. A close structural analogue (HS43) with 5-fold lower affinity for ZIPK produced no effect on cells or tissues. These findings are consistent with a mechanism of action wherein HS38 specifically targets ZIPK in smooth muscle. The discovery of HS38 provides a lead scaffold for the development of therapeutic agents for smooth muscle related disorders and a chemical means to probe the function of DAPK1 and ZIPK across species.

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Published In

ACS Chem Biol

DOI

EISSN

1554-8937

Publication Date

December 20, 2013

Volume

8

Issue

12

Start / End Page

2715 / 2723

Location

United States

Related Subject Headings

  • Recombinant Fusion Proteins
  • Rabbits
  • Pyrimidinones
  • Pyrazoles
  • Proteomics
  • Protein Kinase Inhibitors
  • Primary Cell Culture
  • Phosphorylation
  • Organic Chemistry
  • Myosin-Light-Chain Phosphatase
 

Citation

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Carlson, D. A., Franke, A. S., Weitzel, D. H., Speer, B. L., Hughes, P. F., Hagerty, L., … Haystead, T. A. J. (2013). Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor. ACS Chem Biol, 8(12), 2715–2723. https://doi.org/10.1021/cb400407c
Carlson, David A., Aaron S. Franke, Douglas H. Weitzel, Brittany L. Speer, Philip F. Hughes, Laura Hagerty, Christopher N. Fortner, et al. “Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor.ACS Chem Biol 8, no. 12 (December 20, 2013): 2715–23. https://doi.org/10.1021/cb400407c.
Carlson DA, Franke AS, Weitzel DH, Speer BL, Hughes PF, Hagerty L, et al. Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor. ACS Chem Biol. 2013 Dec 20;8(12):2715–23.
Carlson, David A., et al. “Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor.ACS Chem Biol, vol. 8, no. 12, Dec. 2013, pp. 2715–23. Pubmed, doi:10.1021/cb400407c.
Carlson DA, Franke AS, Weitzel DH, Speer BL, Hughes PF, Hagerty L, Fortner CN, Veal JM, Barta TE, Zieba BJ, Somlyo AV, Sutherland C, Deng JT, Walsh MP, MacDonald JA, Haystead TAJ. Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor. ACS Chem Biol. 2013 Dec 20;8(12):2715–2723.
Journal cover image

Published In

ACS Chem Biol

DOI

EISSN

1554-8937

Publication Date

December 20, 2013

Volume

8

Issue

12

Start / End Page

2715 / 2723

Location

United States

Related Subject Headings

  • Recombinant Fusion Proteins
  • Rabbits
  • Pyrimidinones
  • Pyrazoles
  • Proteomics
  • Protein Kinase Inhibitors
  • Primary Cell Culture
  • Phosphorylation
  • Organic Chemistry
  • Myosin-Light-Chain Phosphatase