1. Structure-Based Designof a Novel Series of Potent, Selective Inhibitors of the Class IPhosphatidylinositol 3-Kinases.
- Author
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Smith, Adrian L., DâAngelo, Noel D., Bo, Yunxin Y., Booker, Shon K., Cee, Victor J., Herberich, Brad, Hong, Fang-Tsao, Jackson, Claire L. M., Lanman, Brian A., Liu, Longbin, Nishimura, Nobuko, Pettus, Liping H., Reed, Anthony B., Tadesse, Seifu, Tamayo, Nuria A., Wurz, Ryan P., Yang, Kevin, Andrews, Kristin L., Whittington, Douglas A., and McCarter, John D.
- Subjects
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DRUG synergism , *PHOSPHATIDYLINOSITOL 3-kinases , *PROTEIN kinase inhibitors , *STRUCTURE-activity relationship in pharmacology , *LABORATORY mice , *TUMOR growth , *RAPAMYCIN - Abstract
A highly selective series of inhibitors of the classI phosphatidylinositol3-kinases (PI3Ks) has been designed and synthesized. Starting fromthe dual PI3K/mTOR inhibitor 5, a structure-based approachwas used to improve potency and selectivity, resulting in the identificationof 54as a potent inhibitor of the class I PI3Ks withexcellent selectivity over mTOR, related phosphatidylinositol kinases,and a broad panel of protein kinases. Compound 54demonstrateda robust PDâPK relationship inhibiting the PI3K/Akt pathwayin vivo in a mouse model, and it potently inhibited tumor growth ina U-87 MG xenograft model with an activated PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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