Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor

Phosphoinositide 3-kinases, delta (PI3Kdelta) and gamma (PI3Kgamma) are enriched in immune cells and regulate the development and function of innate and adaptive immunity. Dual PI3Kdeltagamma inhibitors are considered high value targets for their potential to treat a variety of immune-mediated diseases, but their discovery has been challenging. Here we describe the preclinical pharmacology of HM5023507, an orally active dual inhibitor of deltagamma isoforms in immune signaling. HM5023507 inhibited PI3Kdelta and PI3Kgamma isoforms with greater than 100-fold selectivity against PI3Kalpha and PI3Kbeta in recombinant enzymatic assays and in primary human immune cells with an exquisite selectivity against other targets. HM5023507 attenuated the PI3Kdelta/gamma signaling in human basophils (IC50: 42/340 nmol/L; selectivity ratio ~1:8). HM5023507 attenuated the activation and function of human B and T cells, Th17 differentiation of CD4 T cells in the blood of healthy donors and rheumatoid arthritis patients, and cytokine and IgG production in human T and B cell cocultures, in vitro. Orally dosed HM5023507 attenuated PI3K delta/gamma-mediated immune signaling in the rat in a dose-related manner. In addition, HM5023507 inhibited semiestablished collagen-induced arthritic inflammation in the rats (ED50 of 0.25mg/kg, p.o. BID or 0.5 mg/kg, QD, AUC: 1422 ng/mL*h), improved histopathology- and micro-computed tomography (microCT)-based indices of joint damage, bone destruction, and attenuated the levels of anti-collagen antibody, with an overall anti-inflammatory profile matching that of a TNFalpha neutralizing antibody. The PI3K deltagamma inhibitory profile of HM5023507 and its selectivity make it a useful tool to further delineate immunobiology of dual PI3K deltagamma targeting.