Targeting MAPAKAP2(MK2) to combat inflammation by avoiding the differential regulation of anti-inflammatory genes by p38 MAPK inhibitors

Abstract

p38 mitogen-activated protein kinase (p38 MAPK) plays an important role in the key cellular processes related to inflammation. Several small molecule inhibitors of p38 MAPK therefore have been evaluated for their anti-inflammatory potential and progressed from early discovery to late phase clinical trials. Most of these efforts however have failed due to severe toxicity concerns. Since p38 MAPK has several downstream substrates, inhibition of p38 MAPK, therefore, leads to the modulation of all its substrates, resulting into a dis-balance of pro- and anti-inflammatory response and multiple toxicity concerns. Targeting p38MAPK MAPKAPK2 (MK2), one of the downstream substrates of p38 MAPK directly, is expected to be a better anti-inflammatory approach without having any toxicity concerns. In this manuscript, we are reporting biological data of representative MK2 inhibitor to validate its anti-inflammatory potential and a comparison of p38 MAPK and MK2 inhibitors in cell based assays to understand their relative toxicities.