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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

[Image: see text] 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 K(d) = 7.5...

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Autores principales: 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, de Haven Brandon, Alexis, Raynaud, Florence I., Workman, Paul, Eccles, Suzanne A., Bayliss, Richard, Linardopoulos, Spiros, Blagg, Julian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2012
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483018/
https://www.ncbi.nlm.nih.gov/pubmed/23043539
http://dx.doi.org/10.1021/jm300952s
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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
de Haven Brandon, Alexis
Raynaud, Florence I.
Workman, Paul
Eccles, Suzanne A.
Bayliss, Richard
Linardopoulos, Spiros
Blagg, Julian
author_facet 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
de Haven Brandon, Alexis
Raynaud, Florence I.
Workman, Paul
Eccles, Suzanne A.
Bayliss, Richard
Linardopoulos, Spiros
Blagg, Julian
author_sort Bavetsias, Vassilios
collection PubMed
description [Image: see text] 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 K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 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.
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spelling pubmed-34830182012-10-29 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 de Haven Brandon, Alexis Raynaud, Florence I. Workman, Paul Eccles, Suzanne A. Bayliss, Richard Linardopoulos, Spiros Blagg, Julian J Med Chem [Image: see text] 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 K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 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. American Chemical Society 2012-10-08 2012-10-25 /pmc/articles/PMC3483018/ /pubmed/23043539 http://dx.doi.org/10.1021/jm300952s Text en Copyright © 2012 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.
spellingShingle 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
de Haven Brandon, Alexis
Raynaud, Florence I.
Workman, Paul
Eccles, Suzanne A.
Bayliss, Richard
Linardopoulos, Spiros
Blagg, Julian
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483018/
https://www.ncbi.nlm.nih.gov/pubmed/23043539
http://dx.doi.org/10.1021/jm300952s
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