Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening

[Image: see text] Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively and is informed by biochemical assays. To drive development toward specific oncopathways, compounds were tested...

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Autores principales: Myers, Samuel H., Temps, Carolin, Houston, Douglas R., Brunton, Valerie G., Unciti-Broceta, Asier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851644/
https://www.ncbi.nlm.nih.gov/pubmed/29466002
http://dx.doi.org/10.1021/acs.jmedchem.7b01605
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author Myers, Samuel H.
Temps, Carolin
Houston, Douglas R.
Brunton, Valerie G.
Unciti-Broceta, Asier
author_facet Myers, Samuel H.
Temps, Carolin
Houston, Douglas R.
Brunton, Valerie G.
Unciti-Broceta, Asier
author_sort Myers, Samuel H.
collection PubMed
description [Image: see text] Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively and is informed by biochemical assays. To drive development toward specific oncopathways, compounds were tested against cancer cells that overexpress, or not, AXL kinase. Identified phenotypic hits were found to inhibit oncotargets AXL, RET, and FLT3. Subsequent optimization generated antiproliferative lead compounds with unique selectivity profiles, including selective AXL inhibitors and a highly potent inhibitor of FLT3.
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spelling pubmed-58516442018-03-15 Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening Myers, Samuel H. Temps, Carolin Houston, Douglas R. Brunton, Valerie G. Unciti-Broceta, Asier J Med Chem [Image: see text] Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively and is informed by biochemical assays. To drive development toward specific oncopathways, compounds were tested against cancer cells that overexpress, or not, AXL kinase. Identified phenotypic hits were found to inhibit oncotargets AXL, RET, and FLT3. Subsequent optimization generated antiproliferative lead compounds with unique selectivity profiles, including selective AXL inhibitors and a highly potent inhibitor of FLT3. American Chemical Society 2018-02-21 2018-03-08 /pmc/articles/PMC5851644/ /pubmed/29466002 http://dx.doi.org/10.1021/acs.jmedchem.7b01605 Text en Copyright © 2018 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Myers, Samuel H.
Temps, Carolin
Houston, Douglas R.
Brunton, Valerie G.
Unciti-Broceta, Asier
Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening
title Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening
title_full Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening
title_fullStr Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening
title_full_unstemmed Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening
title_short Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening
title_sort development of potent inhibitors of receptor tyrosine kinases by ligand-based drug design and target-biased phenotypic screening
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851644/
https://www.ncbi.nlm.nih.gov/pubmed/29466002
http://dx.doi.org/10.1021/acs.jmedchem.7b01605
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