Products Cited in Publications Worldwide The Structural Requirements of 3, 5-Substituted Oxindoles that Determine Selective Ampk or Gsk3β Inhibition

The Structural Requirements of 3, 5-Substituted Oxindoles that Determine Selective Ampk or Gsk3β Inhibition

Strang, Juliet E; Astridge, Daniel D; Chandler, Caleb; Reigan, Phil

DOI:

Abstract

AMP-activated protein kinase (AMPK) acts as a central cellular sensor at the interface of metabolic and signaling networks, that supports cell survival in energetically unfavorable environments. Due to its role in the direct mediation of fatty acid oxidation via acetyl-CoA carboxylase 2 (ACC2), there has been intensive development of small molecule activators for the treatment of metabolic diseases, such as and non-alcoholic fatty liver disease. In , inhibitors may be more effective in disrupting catabolic processes that support cell growth and survival. However, there has been little development of inhibitors and those that have been reported have limitations that prevent clinical evaluation. We have previously reported a structure-activity study of substituted oxindoles based on the multi-kinase inhibitor to determine the structural requirements for inhibition and found that a 5-(2-cyanoethyl)-substituted oxindole displayed selectivity for over VEGFR-2. Interestingly, the 5-cyano-oxindole has been reported as a GSK3β inhibitor and was also found to inhibit in a limited screen. Here, we report a further series of 3,5-substituted oxindoles that demonstrate that 5-cyano-oxindoles can inhibit both GSK3β and , but the 5-(2-cyanoethyl)-substitution and the orientation of the 3-substituent of the oxindole are critical determinants for inhibition and selectivity.

Keywords

; GSK3β ; kinase ; oxindole ; small molecule inhibitor

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5-Cyanooxindole

A56141561394-50-195%

5-Cyanooxindole

669.0/25g

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