Discovery of Pyrazolo[1,5-a]pyrimidine derivative as a potent and selective PI3K?/6 dual inhibitor

Phosphoinositol 3-kinases (PI3Ks) & gamma; and 6 are primarily expressed in leukocytes and play crucial roles in regulation of the immune system. Dual inhibition of PI3K & gamma;/6 has emerged as an effective approach to regulate the tumor microenvironment. Here, we report the exploration of structure-activity relationship optimization which led to the discovery of a potent PI3K & gamma;/6 dual inhibitor 15u (IHMT-PI3K-455). 15u exhibits strong potency in biochemical and cellular assays and it repolarizes M2 phenotype toward M1 phenotype in THP-1 and BMDM macrophages. In addition, it shows suitable in vivo properties as demonstrated through pharmacokinetic studies in rats and pharmacodynamics properties in a MC38 xenograft model.