Discovery of Pyrazolo[1,5-a]pyrimidine derivative as a potent and selective PI3K?/6 dual inhibitor

被引：3
|
作者：
Liang, Xiaofei [1 ,2 ]
Deng, Maoqing [1 ,2 ,3 ]
Zou, Fengming [1 ,2 ]
Qi, Ziping [1 ,2 ]
Wang, Chun [1 ,3 ]
Liu, Juan [1 ,2 ]
Liu, Qingwang [1 ,2 ]
Wang, Beilei [1 ,2 ]
Qi, Shuang [1 ,2 ]
Ge, Juan [1 ,3 ]
Yu, Hongwei [1 ,3 ]
Wang, Aoli [1 ,2 ]
Liu, Qingsong [1 ,2 ,3 ,4 ,5 ]
Liu, Jing [1 ,2 ,3 ,4 ,5 ]
机构：
[1] Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Anhui, Peoples R China
[2] Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Anhui, Peoples R China
[3] Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China
[4] Precis Med Res Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China
[5] Chinese Acad Sci, Hefei Inst Phys Sci, Hefei 230031, Anhui, Peoples R China
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 260卷
基金：
中国国家自然科学基金;
关键词：
PI3K-GAMMA; INFLAMMATION; RESISTANCE; PI3K-DELTA; ISOFORM;
D O I：
10.1016/j.ejmech.2023.115768
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Phosphoinositol 3-kinases (PI3Ks) & gamma; and 6 are primarily expressed in leukocytes and play crucial roles in regulation of the immune system. Dual inhibition of PI3K & gamma;/6 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 PI3K & gamma;/6 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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收藏
页数：16
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