Macrophage polarization is a process by which macrophages carry out various functional programs responding to signals. Pyruvate Dehydrogenase Kinase (PDK) is a kinase, phosphorylates pyruvate dehydrogenase with ATP to cause it inactive. ATP, NADH and acetyl-CoA can activate PDK, while ADP, NAD+, CoA-SH and pyruvate are able to inhibit it. PDK1 involves in M1 macrophage polarization through HIF-1α-mediated aerobic glycolysis. PDK2 and PDK4 play important role in metabolic diseases. Deficiency of Pdk2 and Pdk4 reduces pro-inflammatory markers. Thus, it is possible to alleviate inflammatory response via PDK inhibition.

KPLH1130 is a PDK inhibitor. It (5–10 μM) markedly suppresses the expression of pro-inflammatory cytokines. The latter include IL-1β, TNFα, and IL-6. KPLH1130 also potently reduces levels of iNOS, nitric oxide and HIF-1α via PDK in different types of macrophages.

In peritoneal macrophages (PMs) incubated with LPS and IFN-γ, the inhibitor blocks macrophage activation in peritoneal macrophages (PMs) at a concentration of 10 μM.

Besides, M1 polarizing causes decrease in basal and maximal oxygen consumption rate. KPLH1130 has the ability to prevent the effect.

Moreover, KPLH1130 exhibits excellent activity in animals. Mice are pretreated with high-fat diet (HFD). KPLH1130 treatment is at a dose of 70 mg/kg. Animals are administered with the inhibitor for 4 weeks. KPLH1130 significantly enhances the glucose tolerance of HFD-induced mice. Furthermore, anti-inflammtory cytokines results in similar effect to KPLH1130.

In summary, KPLH1130 is a potent pyruvate dehydrogenase kinase inhibitor, with anti-inflammatory activity. Further study needs to be done to find out more potential of the compound.

1. Min BK, et al. Front Immunol. 2019 May 7;10:944.