In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.

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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 imidazole 9 (2‐(3′‐(2‐amino‐2‐oxoethyl)‐[1,1′‐biphenyl]‐3‐yl)‐N‐(5‐(N,N‐dimethylsulfamoyl)‐2‐methylphenyl)‐1‐propyl‐1H‐imidazole‐5‐carboxamide) and the orally bioavailable imidazole 18 (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 although 9 and 18 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.

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The Front Cover shows pillars of drug discovery projects and key questions to ask to avoid getting “lost in translation”. Each project needs a) a hypothesis that modulating protein X could benefit disease Y, b) a design strategy to make leads modulating protein X, and c) a translational screening cascade linking the target and hypothesis. Following structure–activity through the cascade is critical to validate or challenge the project hypothesis. In this case, potent p38 inhibitors were designed to show differential activity on kinases MK2 and MSK1, but this did not translate into preservation of pro‐resolution IL‐10 while inhibiting pro‐inflammatory TNF‐α, contrary to the project hypothesis. More information can be found in the Full Paper by Katerina Pardali, Mickael Mogemark et al. on page 1701 in Issue 19, 2019 (DOI: 10.1002/cmdc.201900303).