کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8294890 | 1536755 | 2018 | 25 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Discovery and characterization of an iminocoumarin scaffold as an inhibitor of MEKK2 (MAP3K2)
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کلمات کلیدی
MEKK2TR-FRETSARHTSADPDMSO - DMSOMAPK - MAPKAdenosine Triphosphate - آدنوزین تری فسفاتATP - آدنوزین تری فسفات یا ATPadenosine diphosphate - آدنوزین دی فسفاتTime-resolved fluorescence resonance energy transfer - انتقال انرژی رزونانس فلورسانس زمان حل شده استstandard deviation - انحراف معیارInhibitor - بازدارندهEnzyme-linked immunosorbent assay - تست الیزاELISA - تست الیزاDimethyl sulfoxide - دیمتیل سولفواکسیدStructure-activity relationship - رابطه ساختار-فعالیتMass spectrometry - طیف سنجی جرمیhigh throughput screening - غربالگری بالاmitogen-activated protein kinase - پروتئین کیناز فعال با mitogenKinase - کیناز
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The kinase MEKK2 (MAP3K2) activates the MEK5/ERK5 cell signaling pathway and may play an important role in tumor growth and metastasis. Thus, MEKK2 may represent a novel kinase target for cancer. In order to identify inhibitors of MEKK2, we screened a library of compounds using a high throughput MEKK2 intrinsic ATPase enzyme assay. We identified two hits with validated structures and confirmed activity in the primary assay (IC50 valuesâ¯=â¯322â¯nM and 7.7â¯Î¼M) and two orthogonal MEKK2 biochemical assays. Compound 1, the more potent hit, was the subject of further investigation. Limited structure-activity relationship (SAR) studies were performed on this iminocoumarin hit which resulted in â¥20-fold more potent analogs (e.g. 8 and 16â¯nM IC50). Two analogs had improved selectivity in a 50-member kinase profiling panel compared to the hit. These studies suggested that substitutions around the phenoxy ring of this scaffold can impart improved potency and selectivity for MEKK2. Analog Compound 1s (16â¯nM IC50) was further verified by external testing to inhibit MEKK2 and MEKK3 with similar potencies. Compound 1s displayed activity in cell-based assays in which it inhibited ERK5 pathway activation in cells and inhibited cell migration in a scratch assay. Thus, we have identified a scaffold that has promising potential to be developed into a highly selective and potent inhibitor of MEKK2. Information from these SAR studies provides specific guidance for the future design of MEKK2 inhibitor probes.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical and Biophysical Research Communications - Volume 496, Issue 1, 29 January 2018, Pages 205-211
Journal: Biochemical and Biophysical Research Communications - Volume 496, Issue 1, 29 January 2018, Pages 205-211
نویسندگان
Syed Ahmad, Valentine R. St. Hilaire, Srinivasa R. Dandepally, Gary L. Johnson, Alfred L. Williams, John E. Scott,