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Competitive inhibition of human Aurora C ATP binding site

PubChem AID
479680
Protein Target
Primary Citation
Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase [PMID: 20420387]
Source
External ID
BioAssay Type
Confirmatory
Tested Substances
Tested Compounds
Version
Status
Live
Dates
  • Deposit:
    2010-09-27
  • Modify:
    2022-08-30
Description
This bioassay record (AID 479680) reports results from the above primary citation. Additional data from the same publication are reported in a total of 55 BioAssay records in PubChem.

1 Description

Title: Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.

Abstract: The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.

2 Comment

Compounds with activity <= 10uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Journal: J Med Chem

Year: 2010

Volume: 53

Issue: 10

First Page: 3973

Last Page: 4001

DOI: 10.1021/jm901870q

Target ChEMBL ID: CHEMBL3935

ChEMBL Target Name: Serine/threonine-protein kinase Aurora-C

ChEMBL Target Type: SINGLE PROTEIN - Target is a single protein chain

Relationship Type: D - Direct protein target assigned

Confidence: Direct single protein target assigned

3 Result Definitions

4 Data Table

5 Target

8 Identity

8.1 BioAssay Name

Competitive inhibition of human Aurora C ATP binding site

8.2 Source

8.3 External ID

8.4 Project Category

Literature, Extracted

8.5 BioAssay Type

Confirmatory

8.6 Deposit Date

2010-09-27

8.7 Modify Date

Version 1.1
Version 1.2
Version 1.3
Version 2.1
Version 2.2
Version 2.3
Version 3.1
Version 4.1
Version 5.1
Version 6.1
Version 6.2
Version 7.1
Version 7.2
Version 7.3
Version 7.4
Version 7.5
Version 8.1
Version 8.2
2022-08-30 (currently shown)

8.8 Status

Live

9 Same-Publication BioAssays

10 BioAssay Annotations

Assay Type
Binding
Assay Organism

11 Information Sources

  1. PubChem
  2. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
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