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

Abstract

Phosphoinositide 3‐kinases, delta (PI3Kδ) and gamma (PI3Kγ) are enriched in immune cells and regulate the development and function of innate and adaptive immunity. Dual PI3Kδγ 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 δγ isoforms in immune signaling. HM5023507 inhibited PI3Kδ and PI3Kγ isoforms with greater than 100‐fold selectivity against PI3Kα and PI3Kβ in recombinant enzymatic assays and in primary human immune cells with an exquisite selectivity against other targets. HM5023507 attenuated the PI3Kδ/γ 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 δ/γ‐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 (µCT)‐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 TNFα neutralizing antibody. The PI3K δγ inhibitory profile of HM5023507 and its selectivity make it a useful tool to further delineate immunobiology of dual PI3K δγ targeting.

Quantitative imaging reveals PI3Kδ inhibition reduces rhinovirus-induced damage of small airway epithelia in ex vivo cultured human precision cut lung slices from COPD patients

“…Previous reports have shown that application of a PI3Kδ inhibitor improved survival rates and decreased IFNγ, IL-1β and IL-10 levels following S. pneumoniae infection in mice with an activating PI3Kδ mutation that symptomatically resembles the COPD phenotype 17 . Similarly, non-selective PI3K inhibition has been demonstrated to reduce IP-10 and IL-8 secretion by RV16-infected primary bronchial epithelial cells and IL-8 secretion by LPS-stimulated COPD blood neutrophils 40 , while selective PI3Kδ inhibition reduced LPS-and TNFα-induced secretion of IL-8 by monocytes from patients with COPD 12,41 , and attenuated IFNγ and IL-2 cytokine secretion by in vitro co-cultures of T-and B-cells from healthy donors 42 . Furthermore, administration of an inhaled PI3Kδ inhibitor to COPD patients with stable disease reduced sputum inflammatory mediators such as IL-8 and IL-13 [43][44][45] and a clinically meaningful improvement in FEV1 45 .…”