Identification of novel inhibitors of Aurora A with a 3-(pyrrolopyridin-2-yl)indazole scaffold

Pinrao Song; Ming Chen; Xiaodong Ma; Lei Xu; Tao Liu; Yubo Zhou; Yongzhou Hu

doi:10.1016/j.bmc.2015.02.004

Identification of novel inhibitors of Aurora A with a 3-(pyrrolopyridin-2-yl)indazole scaffold

Bioorg Med Chem. 2015 Apr 15;23(8):1858-68. doi: 10.1016/j.bmc.2015.02.004. Epub 2015 Feb 13.

Authors

Pinrao Song¹, Ming Chen¹, Xiaodong Ma¹, Lei Xu², Tao Liu³, Yubo Zhou⁴, Yongzhou Hu⁵

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
⁴ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
⁵ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].

PMID: 25771484
DOI: 10.1016/j.bmc.2015.02.004

Abstract

A novel series of 3-(pyrrolopyridin-2-yl)indazole derivatives were synthesized and biologically evaluated for their anti-proliferative effects on five human cancer cell lines. As a result, all of them exhibited vigorous potency against HL60 cell line with IC50 values ranging from singe digital nanomolar to micromolar level. Besides, a majority of them displayed modest to good antiproliferative activities against the other four cell lines, including KB, SMMC-7721, HCT116, and A549. Particularly, compound 2y, as the most distinguished one in this series, demonstrated IC50 values of 8.3nM and 1.3nM against HL60 and HCT116 cell lines, respectively. Afterwards, for exploring the molecular target, compounds2d, 2g and 2y were further selected to evaluate the inhibitory activities against a panel of kinases. Finally, they were identified to be targeting Aurora A kinase with significant selectivity over other kinases, such as CHK1, CDK2, MEK1, GSK3β, BRAF, IKKβ and PKC.

Keywords: Antiproliferative agents; Aurora A inhibitors; Cell cycle profile; Pyrrolopyridin-indazoles; Selectivity.

Publication types

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

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Aurora Kinase A / antagonists & inhibitors*
Aurora Kinase A / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects*
Humans
Indazoles / chemistry*
Indazoles / pharmacology*
Neoplasms / drug therapy
Neoplasms / enzymology*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Indazoles
Protein Kinase Inhibitors
Aurora Kinase A