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

  • J Med Chem. 2024 Sep 12;67(17):15199-15219. doi: 10.1021/acs.jmedchem.4c00817.
Chun Wang  1  2 ,  Fengming Zou  1  3  4 ,  Ziping Qi  1  3  4 ,  Qingwang Liu  1  3  4 ,  Lijuan Shen  1  2 ,  Xinyu Yuan  1  2 ,  Maoqing Deng  1  2 ,  Aoli Wang  1  3  4 ,  Beilei Wang  1  3  4 ,  Li Wang  1  3  4  5 ,  Xiaofei Liang  1  2  3  4 ,  Qingsong Liu  1  2  3  4  5 ,  Jing Liu  1  2  3  4  5
Affiliations
  • 1. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
  • 2. University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.
  • 3. Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
  • 4. Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China.
  • 5. Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China.
PMID: 39163191 DOI: 10.1021/acs.jmedchem.4c00817
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.

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