dc.contributor.author |
Bavetsias, V |
en |
dc.contributor.author |
Large, JM |
en |
dc.contributor.author |
Sun, CB |
en |
dc.contributor.author |
Bouloc, N |
en |
dc.contributor.author |
Kosmopoulou, M |
en |
dc.contributor.author |
Matteucci, M |
en |
dc.contributor.author |
Wilsher, NE |
en |
dc.contributor.author |
Martins, V |
en |
dc.contributor.author |
Reynisson, Johannes |
en |
dc.contributor.author |
Atrash, B |
en |
dc.contributor.author |
Faisal, A |
en |
dc.contributor.author |
Urban, F |
en |
dc.contributor.author |
Valenti, M |
en |
dc.contributor.author |
Brandon, AD |
en |
dc.contributor.author |
Box, G |
en |
dc.contributor.author |
Raynaud, FI |
en |
dc.contributor.author |
Workman, P |
en |
dc.contributor.author |
Eccles, SA |
en |
dc.contributor.author |
Bayliss, R |
en |
dc.contributor.author |
Blagg, J |
en |
dc.contributor.author |
Linardopoulos, S |
en |
dc.contributor.author |
McDonald, E |
en |
dc.date.accessioned |
2012-03-14T00:15:06Z |
en |
dc.date.issued |
2010-07-22 |
en |
dc.identifier.citation |
J Med Chem 53(14):5213-5228 22 Jul 2010 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/14283 |
en |
dc.description.abstract |
Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC50 = 0.015 +/- 0.003 mu M, Aurora-B IC50 = 0.025 mu M, Aurora-C IC50 = 0.019 mu M). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss. |
en |
dc.language |
EN |
en |
dc.publisher |
American Chemical Society |
en |
dc.relation.ispartofseries |
Journal of Medicinal Chemistry |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0022-2623/ |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
SMALL-MOLECULE INHIBITOR |
en |
dc.subject |
IN-VIVO |
en |
dc.subject |
B KINASE |
en |
dc.subject |
COLORECTAL CANCERS |
en |
dc.subject |
ANTICANCER AGENTS |
en |
dc.subject |
DISCOVERY |
en |
dc.subject |
POTENT |
en |
dc.subject |
PHOSPHORYLATION |
en |
dc.subject |
OVEREXPRESSION |
en |
dc.subject |
SPINDLE |
en |
dc.title |
Imidazo[4,5-b]pyridine Derivatives As Inhibitors of Aurora Kinases: Lead Optimization Studies toward the Identification of an Orally Bioavailable Preclinical Development Candidates |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/jm100262j |
en |
pubs.issue |
14 |
en |
pubs.begin-page |
5213 |
en |
pubs.volume |
53 |
en |
dc.rights.holder |
Copyright: American Chemical Society |
en |
dc.identifier.pmid |
20565112 |
en |
pubs.end-page |
5228 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
119845 |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
pubs.record-created-at-source-date |
2010-11-25 |
en |
pubs.dimensions-id |
20565112 |
en |