Abstract
A focused library of hetero-trisubstituted purines was developed for improving the cell penetrating and biological efficacy of a series of anti-Stat3 protein inhibitors. From this SAR study, lead agent 22e was identified as being a promising inhibitor of MM tumour cells (IC50's <5μM). Surprisingly, biophysical and biochemical characterization proved that 22e was not a Stat3 inhibitor. Initial screening against the kinome, prompted by the purine scaffold's history for targeting ATP binding pockets, suggests possible targeting of the JAK family kinases, as well for ABL1 (nonphosphorylated F317L) and AAK1.
Keywords:
Cancer therapeutics; Kinome; Multiple myeloma; Purine scaffold; Stat3.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / analogs & derivatives*
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Adenosine / chemical synthesis
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Adenosine / chemistry
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Adenosine / pharmacology
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Survival / drug effects
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Humans
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Phosphorylation / drug effects
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Purines / chemical synthesis
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Purines / chemistry*
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Purines / pharmacology
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STAT3 Transcription Factor / antagonists & inhibitors*
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STAT3 Transcription Factor / metabolism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology
Substances
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2-(2-((4-cyclohexylbenzyl)amino)-6-((4-fluorophenyl)amino)-9H-purin-9-yl)ethyl sulfamate
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Antineoplastic Agents
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Purines
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STAT3 Transcription Factor
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Sulfonamides
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Adenosine