Discovery and development of dual PI3Kdelta/gamma inhibitors for use as novel anti-inflammatory agents

PI3Kdelta and PI3Kgamma regulate immune cell signaling, while the related PI3Kalpha; and PI3Kbeta; regulate cell survival and metabolism. Selective dual inhibitors of PI3Kdelta and PI3Kgamma; represent a potential class of anti-inflammatory agents lacking the anti-proliferative effects associated with PI3Kalpha and PI3Kbeta inhibition. Here we outline the discovery and synthesis of PI3Kdelta; and PI3Kdelta/gamma dual inhibitors that display up to 1,000-fold selectivity over PI3Kalpha and PI3Kbeta. We explain the criteria for selectivity for PI3Kdelta and PI3Kgamma and evaluate the selective compounds in a high-content inflammation assay using mixtures of primary human cells. We find selective inhibition of only PI3Kdelta is weakly anti-inflammatory, but PI3Kdelta/gamma inhibitors show superior inflammatory marker suppression through suppression of LPS-induced TNFalpha production and T cell activation. Moreover, PI3Kdelta/gamma inhibition yields an anti-inflammatory signature distinct from pan-PI3K inhibition and known anti-inflammatory drugs, yet bears striking similarities to glucocorticoid receptor agonists. These results highlight the potential of selectively designing drugs that target kinases with shared biological function. We also outline the discovery and synthesis of a new set of PI3K inhibitors in which a small change in structure yields an extremely promiscuous molecule in contrast to the much more selective members of the set. We explain the principles behind the extreme selectivity achieved with the PI3Kdelta/gamma and PI3Kdelta inhibitors and hypothesize what led to the extreme promiscuity displayed by one molecule