Discovery of pyrazolopyrimidine derivatives as potent BTK inhibitors with effective anticancer activity in MCL

被引：19

作者：

Ran, Fansheng ^{[1
]}

Liu, Yang ^{[2
]}

Liu, Meixia ^{[1
]}

Zhang, Daoguang ^{[1
]}

Wang, Peng ^{[3
]}

Dong, Junze ^{[1
]}

Tang, Wendi ^{[1
]}

Zhao, Guisen ^{[1
]}

机构：

[1] Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China

[2] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA

[3] Shandong Qidu Pharmaceut Co Ltd, 28 Renmin East Rd, Zibo 255400, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2019年 / 89卷

关键词：

Mantle cell lymphoma; BTK inhibitors; Anticancer; Selectivity; Patient cells; BRUTONS TYROSINE KINASE; MANTLE CELL LYMPHOMA; IBRUTINIB; PATHOGENESIS; ANALOGS;

D O I：

10.1016/j.bioorg.2019.102943

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Bruton's tyrosine kinase (BTK) is a key regulator of B-cell receptor (BCR) signaling pathway and takes effect in the regulation of B-cell activation, survival, proliferation and differentiation. It has been proved that BTK is commonly overexpressed in mantle cell lymphoma (MCL), which makes it a focus of targeted therapy for MCL. Our studies yielded a novel series of pyrazolopyrimidine derivatives capable of potent inhibition of BTK. Notably, 12a showed higher selectivity against BTK and exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells. Low micromolar doses of 12a induced strong cell apoptosis in Jeko-1 and Z138 cells.

引用

页数：9

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