Discovery of Pyrazolo[1,5-<i>a</i>]pyridine Derivatives as Potent and Selective PI3Kγ/δ Inhibitors
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, <b>20e</b> (<b>IHMT-PI3K-315</b>) displays an IC<sub>50</sub> 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 EC<sub>50</sub> values of 0.028 and 0.013 μM in cellular assays. In addition, <b>20e</b> exhibits a favorable selectivity profile in protein kinases at 1 μM. In bone marrow-derived macrophages (BMDM), <b>20e</b> can repolarize the M2 phenotype to the M1 phenotype. In vivo, <b>20e</b> demonstrates acceptable pharmacokinetic properties and suppresses tumor growth in a MC38 syngeneic mouse model.
Authors
- Maoqing Deng
- Xinyu Yuan (ORCID: https://orcid.org/0000-0002-7249-6805)
- Aoli Wang (ORCID: https://orcid.org/0000-0002-2329-2865)
- Xiaofei Liang (ORCID: https://orcid.org/0000-0001-8722-694X)
- Li Wang (ORCID: https://orcid.org/0000-0002-8009-9746)
- Beilei Wang (ORCID: https://orcid.org/0000-0001-9313-1154)
- Chun Wang (ORCID: https://orcid.org/0000-0001-9245-0073)
- Qingwang Liu (ORCID: https://orcid.org/0000-0003-1662-0039)
- Lijuan Shen (ORCID: https://orcid.org/0000-0001-7470-9432)
- Fengming Zou
- Ziping Qi
- Jing Liu (ORCID: https://orcid.org/0000-0001-9513-3591)
Institutions
- University of Science and Technology of China (CN)
- Chinese Academy of Sciences (CN)
- Hefei Institutes of Physical Science (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-08-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c00817
- Citations
- 4
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- National Natural Science Foundation of China
- Youth Innovation Promotion Association of the Chinese Academy of Sciences
- Hefei Institutes of Physical Science, Chinese Academy of Sciences
- Anhui Provincial Key Research and Development Plan
- Major Science and Technology Projects in Anhui Province