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

Fansheng Ran; Yang Liu; Meixia Liu; Daoguang Zhang; Peng Wang; Junze Dong; Wendi Tang; Guisen Zhao

doi:10.1016/j.bioorg.2019.102943

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

Fansheng Ran, Yang Liu, Meixia Liu, Daoguang Zhang, Peng Wang, Junze Dong, Wendi Tang, Guisen Zhao

Lymphoma-Myeloma

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

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.

Original language	English (US)
Article number	102943
Journal	Bioorganic Chemistry
Volume	89
DOIs	https://doi.org/10.1016/j.bioorg.2019.102943
State	Published - Aug 2019

Keywords

Anticancer
BTK inhibitors
Mantle cell lymphoma
Patient cells
Selectivity

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Drug Discovery
Organic Chemistry

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10.1016/j.bioorg.2019.102943

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title = "Discovery of pyrazolopyrimidine derivatives as potent BTK inhibitors with effective anticancer activity in MCL",

abstract = "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.",

keywords = "Anticancer, BTK inhibitors, Mantle cell lymphoma, Patient cells, Selectivity",

author = "Fansheng Ran and Yang Liu and Meixia Liu and Daoguang Zhang and Peng Wang and Junze Dong and Wendi Tang and Guisen Zhao",

note = "Funding Information: This work was supported by the key research and development project of Shandong Province [No. 2017CXGC1401]. Funding Information: This work was supported by the key research and development project of Shandong Province [No. 2017CXGC1401 ]. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = aug,

doi = "10.1016/j.bioorg.2019.102943",

language = "English (US)",

volume = "89",

journal = "Bioorganic Chemistry",

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publisher = "Academic Press Inc.",

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T1 - Discovery of pyrazolopyrimidine derivatives as potent BTK inhibitors with effective anticancer activity in MCL

AU - Ran, Fansheng

AU - Liu, Yang

AU - Liu, Meixia

AU - Zhang, Daoguang

AU - Wang, Peng

AU - Dong, Junze

AU - Tang, Wendi

AU - Zhao, Guisen

N1 - Funding Information: This work was supported by the key research and development project of Shandong Province [No. 2017CXGC1401]. Funding Information: This work was supported by the key research and development project of Shandong Province [No. 2017CXGC1401 ]. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/8

Y1 - 2019/8

N2 - 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.

AB - 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.

KW - Anticancer

KW - BTK inhibitors

KW - Mantle cell lymphoma

KW - Patient cells

KW - Selectivity

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JO - Bioorganic Chemistry

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

Abstract

Keywords

ASJC Scopus subject areas

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