Discovery of Pyrazolo[1,5-a]pyridine Derivatives as Potent and Selective PI3Kγ/δ Inhibitors

PI3K gamma and PI3K delta plays critical roles in exerting immunosuppression by targeting regulatory T cells and myeloid cells. Dual inhibition of PI3K gamma and PI3K delta has emerged as a novel therapeutic strategy for cancer immunotherapy. We herein report a series of pyrazolopyridine derivatives with distinct scaffolds as potent and selective dual inhibitors of PI3K gamma and PI3K delta. Among them, 20e (IHMT-PI3K-315) displays an IC50 value of 4.0 and 9.1 nM against PI3K gamma and PI3K delta respectively in biochemical assays. Meanwhile, it potently inhibits PI3K gamma and PI3K delta-mediated phosphorylation of AKT S473 with EC50 values of 0.028 and 0.013 mu M in cellular assays. In addition, 20e exhibits a favorable selectivity profile in protein kinases at 1 mu M. In bone marrow-derived macrophages (BMDM), 20e can repolarize the M2 phenotype to the M1 phenotype. In vivo, 20e demonstrates acceptable pharmacokinetic properties and suppresses tumor growth in a MC38 syngeneic mouse model.