Design, Synthesis, and Structure-Activity Relationship Studies of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as a New Class of Src Inhibitors with Potent Activities in Models of Triple Negative Breast Cancer

Chun-Hui Zhang; Ming-Wu Zheng; Ya-Ping Li; Xing-Dong Lin; Mei Huang; Lei Zhong; Guo-Bo Li; Rong-Jie Zhang; Wan-Ting Lin; Yan Jiao; Xiao-Ai Wu; Jiao Yang; Rong Xiang; Li-Juan Chen; Ying-Lan Zhao; Wei Cheng; Yu-Quan Wei; Sheng-Yong Yang

doi:10.1021/acs.jmedchem.5b00270

Design, Synthesis, and Structure-Activity Relationship Studies of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as a New Class of Src Inhibitors with Potent Activities in Models of Triple Negative Breast Cancer

J Med Chem. 2015 May 14;58(9):3957-74. doi: 10.1021/acs.jmedchem.5b00270. Epub 2015 Apr 16.

Authors

Chun-Hui Zhang¹, Ming-Wu Zheng¹, Ya-Ping Li¹, Xing-Dong Lin¹, Mei Huang¹, Lei Zhong¹, Guo-Bo Li¹, Rong-Jie Zhang¹, Wan-Ting Lin¹, Yan Jiao¹, Xiao-Ai Wu¹, Jiao Yang¹, Rong Xiang², Li-Juan Chen¹, Ying-Lan Zhao¹, Wei Cheng¹, Yu-Quan Wei¹, Sheng-Yong Yang¹

Affiliations

¹ †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
² ‡Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China.

PMID: 25835317
DOI: 10.1021/acs.jmedchem.5b00270

Abstract

A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were designed and synthesized. Structure-activity relationship (SAR) analysis of these compounds led to the discovery of compound 1j, which showed the highest inhibitory potency against the Src kinase and the most potent antiviability activity against the typical TNBC cell line MDA-MB-231 among all the synthesized compounds. Further kinase inhibition assays showed that compound 1j was a multikinase inhibitor and potently inhibited Src (IC50 = 0.0009 μM) and MAPK signaling protein kinases B-RAF and C-RAF. In an MDA-MB-231 xenograft mouse model, a once-daily dose of compound 1j at 30 mg/kg for 18 days completely suppressed the tumor growth with a tumor inhibition rate larger than 100% without obvious toxicity. It also displayed good pharmacokinetic properties in a preliminary pharmacokinetic assay. Western blot and immunohistochemical assays revealed that compound 1j significantly inhibited Src and MAPK signaling and markedly induced apoptosis in tumor tissues.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylene / analogs & derivatives*
Acetylene / chemistry*
Acetylene / pharmacokinetics
Acetylene / pharmacology
Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Benzamides / chemistry*
Benzamides / pharmacokinetics
Benzamides / pharmacology
Cell Cycle / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Drug Design
Drug Screening Assays, Antitumor
Heterografts
Humans
Male
Mice, SCID
Neoplasm Transplantation
Pyrazoles / chemistry*
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / pathology
src-Family Kinases / antagonists & inhibitors*
src-Family Kinases / chemistry

Substances

3-((4-amino-1-ethyl-1H-pyrazolo(3,4-d)pyrimidin-3-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Antineoplastic Agents
Benzamides
Pyrazoles
Pyrimidines
src-Family Kinases
Acetylene