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Goodwin NC, Cianchetta G, Burgoon HA, et al. Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation. ACS Med Chem Lett. 2014;6(1):53-7doi: 10.1021/ml500242y.
Goodwin, N. C., Cianchetta, G., Burgoon, H. A., Healy, J., Mabon, R., Strobel, E. D., Allen, J., Wang, S., Hamman, B. D., & Rawlins, D. B. (2015). Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation. ACS medicinal chemistry letters, 6(1), 53-7. https://doi.org/10.1021/ml500242y
Goodwin, Nicole C, et al. "Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation." ACS medicinal chemistry letters vol. 6,1 (2015): 53-7. doi: https://doi.org/10.1021/ml500242y
Goodwin NC, Cianchetta G, Burgoon HA, Healy J, Mabon R, Strobel ED, Allen J, Wang S, Hamman BD, Rawlins DB. Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation. ACS Med Chem Lett. 2014 Aug 07;6(1):53-7. doi: 10.1021/ml500242y. eCollection 2015 Jan 08. PMID: 25589930; PMCID: PMC4291701.
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ACS Med Chem Lett. 2014 Aug 07;6(1):53-7. doi: 10.1021/ml500242y. eCollection 2015 Jan 08.

Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.

ACS medicinal chemistry letters

Nicole C Goodwin, Giovanni Cianchetta, Hugh A Burgoon, Jason Healy, Ross Mabon, Eric D Strobel, Jason Allen, Shuli Wang, Brian D Hamman, David B Rawlins

Affiliations

  1. Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
  2. Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.

PMID: 25589930 PMCID: PMC4291701 DOI: 10.1021/ml500242y

Abstract

The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be noncompetitive with ATP, suggesting allosteric inhibition. X-ray crystallography confirmed that these sulfonamides are a rare example of a type III kinase inhibitor that binds away from the highly conserved hinge region and instead resides in the hydrophobic pocket formed in the DFG-out conformation of the kinase, thus accounting for the high level of selectivity observed.

Keywords: DFG-out; LIM kinase 2; allosteric; noncompetitive; selective; type III kinase inhibitor

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