Glucolipotoxicity (GLT), in which elevated levels of glucose and fatty acids have deleterious effects on β-cell biology, is thought to be one of the major contributors in progression of type 2 diabetes. In search of novel small molecules that protect β-cells against GLT, we previously discovered KD025, an inhibitor of Rho-associated coiled-coil–containing kinase isoform 2 (ROCK2), as a GLT-protective compound in INS-1E cells and dissociated human islets. To further understand the mechanism of action of KD025, we found that pharmacological and genetic inhibition of ROCK2 was not responsible for the protective effects of KD025 against GLT. Instead, kinase profiling revealed that KD025 potently inhibits catalytic subunits of casein kinase 2 (CK2), a constitutively active serine/threonine kinase. We experimentally verified that the inhibition of one of the catalytic subunits of casein kinase 2, CK2A1, but not CK2A2, improved cell viability when challenged with GLT. We conclude that KD025 inhibits CK2 to protect β-cells from GLT.

Article Highlights
  • We previously identified the small molecule KD025 in a high-throughput phenotypic screen and found that it protects both rodent cell lines and human islets from the deleterious effects of glucolipotoxicity.

  • Here, we focus on the mechanism of action of KD025.

  • KD025 inhibits casein kinase 2 to protect β-cells against glucolipotoxicity.

  • Due to limited therapeutic options to protect β-cell loss in type 2 diabetes, selective inhibition of casein kinase 2 maybe a potential therapeutic strategy to preserve β-cell dysfunction in type 2 diabetes.

This article contains supplementary material online at https://doi.org/10.2337/figshare.24968748.

R.D. and J.C.S. contributed equally.

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