Discovery of Pyrazolo[1,5-a]pyrimidine derivative as a potent and selective PI3Kγ/δ dual inhibitor

  • Eur J Med Chem. 2023 Nov 15;260:115768. doi: 10.1016/j.ejmech.2023.115768.
Xiaofei Liang  1 ,  Maoqing Deng  2 ,  Fengming Zou  1 ,  Ziping Qi  1 ,  Chun Wang  2 ,  Juan Liu  1 ,  Qingwang Liu  1 ,  Beilei Wang  1 ,  Shuang Qi  1 ,  Juan Ge  2 ,  Hongwei Yu  2 ,  Aoli Wang  1 ,  Qingsong Liu  3 ,  Jing Liu  4
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, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
  • 2. 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, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China.
  • 3. 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, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China.
  • 4. 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, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China. Electronic address: [email protected].
PMID: 37683362 DOI: 10.1016/j.ejmech.2023.115768
Abstract

Phosphoinositol 3-kinases (PI3Ks) γ and δ are primarily expressed in leukocytes and play crucial roles in regulation of the immune system. Dual inhibition of PI3Kγ/δ has emerged as an effective approach to regulate the tumor microenvironment. Here, we report the exploration of structure-activity relationship optimization which led to the discovery of a potent PI3Kγ/δ dual inhibitor 15u (IHMT-PI3K-455). 15u exhibits strong potency in biochemical and cellular assays and it repolarizes M2 phenotype toward M1 phenotype in THP-1 and BMDM macrophages. In addition, it shows suitable in vivo properties as demonstrated through pharmacokinetic studies in rats and pharmacodynamics properties in a MC38 xenograft model.

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