An Angle on MK2 Inhibition—Optimization and Evaluation of Prevention of Activation Inhibitors. (13th August 2019)

• Record Type: Journal Article
• Authors: Hedström, Ulf; Norberg, Monica; Evertsson, Emma; Lever, Sarah R.; Munck af Rosenschöld, Magnus; Lönn, Hans; Bold, Peter; Käck, Helena; Berntsson, Pia; Vinblad, Johanna; Liu, Jianming; Welinder, Anette; Karlsson, Johan; Snijder, Arjan; Pardali, Katerina; Andersson, Ulf; Davis, Andrew M.; Mogemark, Mickael
• Is Part Of: ChemMedChem. Volume 14:Number 19(2019)
• Page Start: 1701
• Page End: 1709
• Publication Date: 2019-08-13
• Subjects: drug discovery -- kinase inhibitors -- ligand design -- mode of action -- prevention of activation; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900303
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: The mitogen‐activated protein kinase p38α pathway has been an attractive target for the treatment of inflammatory conditions such as rheumatoid arthritis. While a number of p38α inhibitors have been taken to the clinic, they have been limited by their efficacy and toxicological profile. A lead identification program was initiated to selectively target prevention of activation (PoA) of mitogen‐activated protein kinase‐activated protein kinase 2 (MK2) rather than mitogen‐ and stress‐activated protein kinase 1 (MSK1), both immediate downstream substrates of p38α, to improve the efficacy/safety profile over direct p38α inhibition. Starting with a series of pyrazole amide PoA MK2 inhibitor leads, and guided by structural chemistry and rational design, a highly selective imidazole9 (2‐(3′‐(2‐amino‐2‐oxoethyl)‐[1, 1′‐biphenyl]‐3‐yl)‐ N ‐(5‐( N, N ‐dimethylsulfamoyl)‐2‐methylphenyl)‐1‐propyl‐1 H ‐imidazole‐5‐carboxamide) and the orally bioavailable imidazole18 (3‐methyl‐ N ‐(2‐methyl‐5‐sulfamoylphenyl)‐2‐( o ‐tolyl)imidazole‐4‐carboxamide) were discovered. The PoA concept was further evaluated by protein immunoblotting, which showed that the optimized PoA MK2 compounds, despite their biochemical selectivity against MSK1 phosphorylation, behaved similarly to p38 inhibitors in cellular signaling. This study highlights the importance of selective tool compounds in untangling complex signaling pathways, and although9 and18 were not differentiated from p38α inhibitors in a cellular context, they are still useful tools for further research directed to understand the role of MK2 in the p38α signaling pathway. Abstract : PoA unveils MoA : The p38α pathway is an attractive target for inflammation research. Cellular signaling downstream of p38α was probed using optimized pyrazole amide MK2 prevention of activation (PoA) inhibitors. Despite biochemical selectivity blocking p38 phosphorylation of MK2 versus MSK1, in cells PoA MK2 and p38 inhibitors behaved similarly. This study highlights the importance of selective tool compounds in untangling complex cellular signaling pathways.