Discovery of novel pyrazole derivatives as potential anticancer agents in MCL

Fansheng Ran; Yang Liu; Daoguang Zhang; Meixia Liu; Guisen Zhao

doi:10.1016/j.bmcl.2019.03.005

Discovery of novel pyrazole derivatives as potential anticancer agents in MCL

Fansheng Ran, Yang Liu, Daoguang Zhang, Meixia Liu, Guisen Zhao

Lymphoma-Myeloma

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

23 Scopus citations

Abstract

Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) (q13;q32), resulting in the overexpression of cyclin-D1. The progression of MCL is an interaction of multitarget and multilink regulation. It has been proven that Bruton's tyrosine kinase (BTK) is commonly overexpressed in MCL, which makes it a focus of targeted therapy for MCL. Irreversible inhibitors usually have great potency, rapid onset of inhibition and long duration of drug action. Herein, structural modification via an open-loop strategy based on lead compound ibrutinib (IBN) was performed, leading to a series of pyrazole derivatives. Compounds 19c, 19′c, 21c and 21′c showed potent effect in MCL cells with IC ₅₀ values lower than 1 μM, and a more than 3-28-fold increase in antiproliferative activity compared with IBN.

Original language	English (US)
Pages (from-to)	1060-1064
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	9
DOIs	https://doi.org/10.1016/j.bmcl.2019.03.005
State	Published - May 1 2019

Keywords

Anticancer
BTK
Irreversible inhibitors
Mantle cell lymphoma
Pyrazole derivatives

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2019.03.005

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title = "Discovery of novel pyrazole derivatives as potential anticancer agents in MCL",

abstract = " Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) (q13;q32), resulting in the overexpression of cyclin-D1. The progression of MCL is an interaction of multitarget and multilink regulation. It has been proven that Bruton's tyrosine kinase (BTK) is commonly overexpressed in MCL, which makes it a focus of targeted therapy for MCL. Irreversible inhibitors usually have great potency, rapid onset of inhibition and long duration of drug action. Herein, structural modification via an open-loop strategy based on lead compound ibrutinib (IBN) was performed, leading to a series of pyrazole derivatives. Compounds 19c, 19′c, 21c and 21′c showed potent effect in MCL cells with IC 50 values lower than 1 μM, and a more than 3-28-fold increase in antiproliferative activity compared with IBN.",

keywords = "Anticancer, BTK, Irreversible inhibitors, Mantle cell lymphoma, Pyrazole derivatives",

author = "Fansheng Ran and Yang Liu and Daoguang Zhang and Meixia Liu and Guisen Zhao",

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AU - Ran, Fansheng

AU - Liu, Yang

AU - Zhang, Daoguang

AU - Liu, Meixia

AU - Zhao, Guisen

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) (q13;q32), resulting in the overexpression of cyclin-D1. The progression of MCL is an interaction of multitarget and multilink regulation. It has been proven that Bruton's tyrosine kinase (BTK) is commonly overexpressed in MCL, which makes it a focus of targeted therapy for MCL. Irreversible inhibitors usually have great potency, rapid onset of inhibition and long duration of drug action. Herein, structural modification via an open-loop strategy based on lead compound ibrutinib (IBN) was performed, leading to a series of pyrazole derivatives. Compounds 19c, 19′c, 21c and 21′c showed potent effect in MCL cells with IC 50 values lower than 1 μM, and a more than 3-28-fold increase in antiproliferative activity compared with IBN.

AB - Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) (q13;q32), resulting in the overexpression of cyclin-D1. The progression of MCL is an interaction of multitarget and multilink regulation. It has been proven that Bruton's tyrosine kinase (BTK) is commonly overexpressed in MCL, which makes it a focus of targeted therapy for MCL. Irreversible inhibitors usually have great potency, rapid onset of inhibition and long duration of drug action. Herein, structural modification via an open-loop strategy based on lead compound ibrutinib (IBN) was performed, leading to a series of pyrazole derivatives. Compounds 19c, 19′c, 21c and 21′c showed potent effect in MCL cells with IC 50 values lower than 1 μM, and a more than 3-28-fold increase in antiproliferative activity compared with IBN.

KW - Anticancer

KW - BTK

KW - Irreversible inhibitors

KW - Mantle cell lymphoma

KW - Pyrazole derivatives

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Discovery of novel pyrazole derivatives as potential anticancer agents in MCL

Abstract

Keywords

ASJC Scopus subject areas

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