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 IC50 value 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 EC50 values of 0.028 and 0.013 μM in cellular assays. In addition, 20e exhibits a favorable selectivity profile in protein kinases at 1 μM. 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.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Class I Phosphatidylinositol 3-Kinases* / antagonists & inhibitors
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Class I Phosphatidylinositol 3-Kinases* / metabolism
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Class Ib Phosphatidylinositol 3-Kinase* / metabolism
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Drug Discovery
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Humans
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Molecular Docking Simulation
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Phosphoinositide-3 Kinase Inhibitors* / chemical synthesis
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Phosphoinositide-3 Kinase Inhibitors* / chemistry
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Phosphoinositide-3 Kinase Inhibitors* / pharmacokinetics
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Phosphoinositide-3 Kinase Inhibitors* / pharmacology
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Pyrazoles* / chemical synthesis
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Pyrazoles* / chemistry
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Pyrazoles* / pharmacokinetics
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Pyrazoles* / pharmacology
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Pyridines* / chemical synthesis
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Pyridines* / chemistry
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Pyridines* / pharmacokinetics
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Pyridines* / pharmacology
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Structure-Activity Relationship
Substances
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Pyridines
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Phosphoinositide-3 Kinase Inhibitors
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Pyrazoles
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Class Ib Phosphatidylinositol 3-Kinase
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Class I Phosphatidylinositol 3-Kinases
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Protein Kinase Inhibitors
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Antineoplastic Agents
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PIK3CG protein, human
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PIK3CD protein, human
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pyrazolopyridine