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).

The mitogen-activated protein kinase p38 alpha pathway has been an attractive target for the treatment of inflammatory conditions such as rheumatoid arthritis. While a number of p38 alpha 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 p38 alpha, to improve the efficacy/safety profile over direct p38 alpha 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 p38 alpha inhibitors in a cellular context, they are still useful tools for further research directed to understand the role of MK2 in the p38 alpha signaling pathway.

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.

A practical one-pot C-H activation/borylation/oxidation sequence for the generation of 3,5-disubstituted phenols is presented. Specifically, 3-bromo-5-methylphenol is prepared from 3-bromotoluene, without isolation of intermediates, on a multigram scale, and in high yield. The process proceeds under mild conditions and can be completed within one day.

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Advances in the development of cross-coupling protocols that avoid haloaromatics are reviewed. Most of the reports that are discussed appeared in the literature within the past 2 years and describe either alternatives to halogenated electrophiles or halogen-free preparations of the organometallic partners. However, while this review is not limited to cross-couplings that are entirely free of haloaromatics, coverage of the topic is largely restricted to reactions affording new aryl-aryl, aryl-heteroaryl and heteroaryl-heteroaryl carbon-carbon bonds during the cross-coupling event.

Ansamycins, including geldanamycin and the derivative 17-allylamino-17-demethoxygeldanamycin, and radicicol are known for their ability to tightly bind to the ATP-binding site of the amino-terminal domain region of heat shock protein 90. We have found that geldanamycin and some of its derivatives can inhibit hepatocyte growth factor/scatter factor-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation at femtomolar levels. Assessment is made of structural requirements for such an activity and evidence is given that distinguishes the target of such an activity from that of heat shock protein 90.