Picky Inhibitors for PI3K

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Science  07 Oct 2005:
Vol. 310, Issue 5745, pp. 19-21
DOI: 10.1126/science.310.5745.19e

Selective inhibition of signaling pathways that lead to inflammation represents a major goal of drug discovery. Because of their regulation of multiple signaling pathways, the phosphoinositide 3-kinase (PI3K) enzymes are particularly attractive targets, although so far the selectivity and efficacy of PI3K inhibitors have been modest.

Using structure-based design, Camps et al. identify small molecules that inhibit the gamma isoform of PI3K and not PI3K α, β, or δ; AS-605240 displayed specificity and potency, preventing phosphorylation of the downstream mediator protein kinase B in vitro. Oral administration of this inhibitor impeded joint inflammation in two experimental rodent models of rheumatoid arthritis. The corresponding reduction in neutrophil infiltration seen in the inflamed joints was consistent with the inhibitory effects of AS-605240 on monocyte and neutrophil chemotaxis in vitro and in vivo. In another study, Barber et al. found that oral dosing of the same inhibitor diminished the severity of an experimental form of the autoimmune disease systemic lupus erythromatosis. Both studies suggest that treatment of inflammatory conditions in humans might be improved through the selective targeting of this and other PI3K pathways. — SJS

Nature Med. 9, 936; 933 (2005).

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