Discovery of\nPyrazolo[1,5‑<i>a</i>]pyridine Derivatives as Potent\nand Selective PI3Kγ/δ\nInhibitors

PI3Kγ and PI3Kδ plays critical roles in exerting\nimmunosuppression\nby targeting regulatory T cells and myeloid cells. Dual inhibition\nof PI3Kγ and PI3Kδ has emerged as a novel therapeutic\nstrategy for cancer immunotherapy. We herein report a series of pyrazolopyridine\nderivatives with distinct scaffolds as potent and selective dual inhibitors\nof PI3Kγ and PI3Kδ. Among them, <b>20e</b> (<b>IHMT-PI3K-315</b>) displays an IC<sub>50</sub> value of 4.0 and\n9.1 nM against PI3Kγ and PI3Kδ respectively in biochemical\nassays. Meanwhile, it potently inhibits PI3Kγ and PI3Kδ-mediated\nphosphorylation of AKT S473 with EC<sub>50</sub> values of 0.028 and\n0.013 μM in cellular assays. In addition, <b>20e</b> exhibits\na favorable selectivity profile in protein kinases at 1 μM.\nIn bone marrow-derived macrophages (BMDM), <b>20e</b> can repolarize\nthe M2 phenotype to the M1 phenotype. In vivo, <b>20e</b> demonstrates\nacceptable pharmacokinetic properties and suppresses tumor growth\nin a MC38 syngeneic mouse model.