1. Discovery of Pyrazolo[1,5-a]pyridine Derivatives as Potent and Selective PI3Kγ/δ Inhibitors
- Author
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Wang, Chun, Zou, Fengming, Qi, Ziping, Liu, Qingwang, Shen, Lijuan, Yuan, Xinyu, Deng, Maoqing, Wang, Aoli, Wang, Beilei, Wang, Li, Liang, Xiaofei, Liu, Qingsong, and Liu, Jing
- Abstract
PI3Kγ and PI3Kδ plays critical roles in exerting immunosuppression by targeting regulatory T cells and myeloid cells. Dual inhibition of PI3Kγ and PI3Kδ 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 PI3Kγ and PI3Kδ. Among them, 20e(IHMT-PI3K-315) displays an IC50value of 4.0 and 9.1 nM against PI3Kγ and PI3Kδ respectively in biochemical assays. Meanwhile, it potently inhibits PI3Kγ and PI3Kδ-mediated phosphorylation of AKT S473 with EC50values of 0.028 and 0.013 μM in cellular assays. In addition, 20eexhibits a favorable selectivity profile in protein kinases at 1 μM. In bone marrow-derived macrophages (BMDM), 20ecan repolarize the M2 phenotype to the M1 phenotype. In vivo, 20edemonstrates acceptable pharmacokinetic properties and suppresses tumor growth in a MC38 syngeneic mouse model.
- Published
- 2024
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