American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation.

We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide 3-kinase γ (PI3Kγ) with efficacy in in vitro and in vivo models of inflammation. Extensive target- and cell-based profiling of CZC24832 revealed regulation of interleukin-17-producing T helper cell (T(H)17) differentiation by PI3Kγ, thus reinforcing selective inhibition of PI3Kγ as a potential treatment for inflammatory and autoimmune diseases.

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Highlights d SAR441255 showed substantial body weight loss in diabetic obese monkeys d SAR441255 also improved glucose control in diabetic obese monkeys d PET imaging in monkeys confirmed high receptor occupancy with SAR441255 d In healthy subjects, biomarkers confirmed engagement of the three receptors by SAR441255

Th17 cells are a lineage of CD4+ T cells characterized by IL-17 secretion, which plays a crucial role in immune responses against important respiratory pathogens, such as Mycobacterium tuberculosis. In this study, we demonstrated that intranasal (i.n.) immunization leads per se to Th17-biased immune responses, regardless of the adjuvant used. The activated CD4+ T cells also showed an up-regulated expression of the chemokine receptor CCR6, which is a marker for murine Th17 cells. These results have important implications in the context of optimizing rational vaccine design, since i.n. immunization appears to be the strategy of choice for situations where the induction of a Th17 phenotype would be beneficial.