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 ~

SUBMITTER: Cai Y 

PROVIDER: S-EPMC6957347 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature