Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 12, Issue 17, Pages 4749-4759Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2004.06.022
Keywords
PI3-K; inhibitor; isoform; phosphatidylinositol
Funding
- NCI NIH HHS [CA 52995] Funding Source: Medline
- NIAID NIH HHS [AI 440099] Funding Source: Medline
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Phosphoinositide 3-kinases (PI3-Ks) are an ubiquitous class of signaling enzymes that regulate diverse cellular processes including growth, differentiation, and motility. Physiological roles of PI3-Ks have traditionally been assigned using two pharmacological inhibitors, LY294002 and wortmannin. Although these compounds are broadly specific for the PI3-K family, they show little selectivity among family members, and the development of isoform-specific inhibitors of these enzymes has been long anticipated. Herein, we prepare compounds from two classes of arylmorpholine PI3-K inhibitors and characterize their specificity against a comprehensive panel of targets within the PI3-K family. We identify multiplex inhibitors that potently inhibit distinct subsets of PI3-K isoforms, including the first selective inhibitor of p110beta/p110delta (IC50 p110beta = 0.13 muM, p110delta = 0.63 muM). We also identify trends that suggest certain PI3-K isoforms may be more sensitive to potent inhibition by arylmorpholines, thereby guiding future drug design based on this pharmacophore. (C) 2004 Elsevier Ltd. All rights reserved.
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