Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia

Bavetsias, Vassilios, Crumpler, Simon, Sun, Chongbo, Avery, Sian, Atrash, Butrus, Faisal, Amir, Moore, Andrew S., Kosmopoulou, Magda, Brown, Nathan, Sheldrake, Peter W., Bush, Katherine, Henley, Alan, Box, Gary, Valenti, Melanie, Brandon, Alexis de Haven, Raynaud, Florence I., Workman, Paul, Eccles, Suzanne A., Bayliss, Richard, Linardopoulos, Spiros and Blagg, Julian (2012) Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia. Journal of Medicinal Chemistry, 55 20: 8721-8734. doi:10.1021/jm300952s


Author Bavetsias, Vassilios
Crumpler, Simon
Sun, Chongbo
Avery, Sian
Atrash, Butrus
Faisal, Amir
Moore, Andrew S.
Kosmopoulou, Magda
Brown, Nathan
Sheldrake, Peter W.
Bush, Katherine
Henley, Alan
Box, Gary
Valenti, Melanie
Brandon, Alexis de Haven
Raynaud, Florence I.
Workman, Paul
Eccles, Suzanne A.
Bayliss, Richard
Linardopoulos, Spiros
Blagg, Julian
Title Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia
Formatted title
Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2012-10-25
Sub-type Article (original research)
DOI 10.1021/jm300952s
Volume 55
Issue 20
Start page 8721
End page 8734
Total pages 14
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2013
Language eng
Formatted abstract
Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A Kd = 7.5 nM, Aurora-B Kd = 48 nM), FLT3 kinase (Kd = 6.2 nM), and FLT3 mutants including FLT3-ITD (Kd = 38 nM) and FLT3(D835Y) (Kd = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20–35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4–11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Non HERDC
 
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Created: Fri, 01 Mar 2013, 11:49:00 EST by Andrew Moore on behalf of Child Health Research Centre