학술논문
Potent and Highly SelectiveBenzimidazole Inhibitorsof PI3-Kinase Delta.
Document Type
Article
Author
Murray, Jeremy M.; Sweeney, Zachary K.; Chan, Bryan K.; Balazs, Mercedesz; Bradley, Erin; Castanedo, Georgette; Chabot, Christine; Chantry, David; Flagella, Michael; Goldstein, David M.; Kondru, Rama; Lesnick, John; Li, Jun; Lucas, Matthew C.; Nonomiya, Jim; Pang, Jodie; Price, Stephen; Salphati, Laurent; Safina, Brian; Savy, Pascal P. A.
Source
Subject
*BENZIMIDAZOLES
*ENZYME inhibitors
*INFLAMMATION treatment
*PHARMACOKINETICS
*TARGETED drug delivery
*DRUG design
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Language
ISSN
0022-2623
Abstract
Inhibition of PI3Kδ is considered to be an attractivemechanismfor the treatment of inflammatory diseases and leukocyte malignancies.Using a structure-based design approach, we have identified a seriesof potent and selective benzimidazole-based inhibitors of PI3Kδ.These inhibitors do not occupy the selectivity pocket between Trp760and Met752 that is induced by other families of PI3Kδ inhibitors.Instead, the selectivity of the compounds for inhibition of PI3Kδrelative to other PI3K isoforms appears to be due primarily to thestrong interactions these inhibitors are able to make with Trp760in the PI3Kδ binding pocket. The pharmacokinetic propertiesand the ability of compound 5to inhibit the functionof B-cells in vivo are described. [ABSTRACT FROM AUTHOR]