US EPA

7456532 

Journal Article 

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

Song, P; Chen, M; Ma, X; Xu, L; Liu, T; Zhou, Y; Hu, Y 

2015 

Yes 

Bioorganic & Medicinal Chemistry
ISSN: 0968-0896
EISSN: 1464-3391 

Elsevier Ltd 

23 

8 

1858-1868 

English 

10.1016/j.bmc.2015.02.004 

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 8.3 nM and 1.3 nM 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. © 2015 Elsevier Ltd. All rights reserved. 

Antiproliferative agents; Aurora A inhibitors; Cell cycle profile; Pyrrolopyridin-indazoles; Selectivity; 1h indazole; 1h indazole 6 carbonitrile; 3 (tributylstannyl) 1h indazole 6 carbonitrile; 3 iodo 1h indazole; 3 iodo 1h indazole 6 carbonitrile; 3 tributylstannyl 1h indazole; 6 chloro 1h indazole; 6 chloro 3 (tributylstannyl) 1h indazole; 6 chloro 3 iodo 1h indazole; antimitotic agent; aurora A kinase; B Raf kinase; checkpoint kinase 1; cyclin dependent kinase 2; glycogen synthase kinase 3beta; I kappa B kinase beta; indazole 6 methyl 5 nitropyridin 2 amine; indazole derivative; mitogen activated protein kinase kinase 1; molecular scaffold; protein kinase C; tert butyl 3 (tributylstannyl) 1h indazole 1 carboxylate; tert butyl 5 [(tert butoxycarbonyl)(methyl)amino] 1h pyrrolo[3,2 b] pyridine 1 carboxylate; tert butyl 6 chloro 3 (tributylstannyl) 1h indazole 1 carboxylate; tert butyl 6 cyano 3 (tributylstannyl) 1h indazole 1 carboxylate; tert butyl methyl(1h pyrrolo[3,2 b]pyridin 5 yl)carbamate; tert butyl methyl(6 methyl 5 nitropyridin 2 yl)carbamate; tert butyl(6 methyl 5 nitropyridin 2 yl)carbamate; unclassified drug; antineoplastic agent; aurora A kinase; indazole derivative; protein kinase inhibitor; A549 cell line; antiproliferative activity; Article; bioassay; cancer inhibition; cell cycle progression; controlled study; drug determination; drug effect; drug identification; drug potency; drug selectivity; drug structure; drug synthesis; drug targeting; enzyme inhibition; HCT116 cell line; human; human cell; IC50; KB cell line; molecular docking; protein targeting; antagonists and inhibitors; cell proliferation; chemistry; drug effects; enzymology; metabolism; Neoplasms; structure activity relation; tumor cell line; Antineoplastic Agents; Aurora Kinase A; Cell Line, Tumor; Cell Proliferation; Humans; Indazoles; Neoplasms; Protein Kinase Inhibitors; Structure-Activity Relationship