Rational Design of Phosphoinositide 3-Kinase α Inhibitors That Exhibit Selectivity over the Phosphoinositide 3-Kinase β Isoform

Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kβ selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2011-11, Vol.54 (22), p.7815-7833
Main Authors: Heffron, Timothy P, Wei, BinQing, Olivero, Alan, Staben, Steven T, Tsui, Vickie, Do, Steven, Dotson, Jennafer, Folkes, Adrian J, Goldsmith, Paul, Goldsmith, Richard, Gunzner, Janet, Lesnick, John, Lewis, Cristina, Mathieu, Simon, Nonomiya, Jim, Shuttleworth, Stephen, Sutherlin, Daniel P, Wan, Nan Chi, Wang, Shumei, Wiesmann, Christian, Zhu, Bing-Yan
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Benzoxepins - chemistry
Benzoxepins - pharmacokinetics
Benzoxepins - pharmacology
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Class I Phosphatidylinositol 3-Kinases - chemistry
Crystallography, X-Ray
Drug Design
Drug Screening Assays, Antitumor
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Humans
Hydrogen Bonding
Isoenzymes - antagonists & inhibitors
Isoenzymes - chemistry
Mice
Models, Molecular
Piperazines - chemistry
Piperazines - pharmacokinetics
Piperazines - pharmacology
Protein Conformation
Pyrimidines - chemistry
Pyrimidines - pharmacokinetics
Pyrimidines - pharmacology
Rats
Structure-Activity Relationship
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Summary:Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kβ selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3Kα that is not attained with the corresponding Lys777 of PI3Kβ. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm2007084