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.

引用

页数：16

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