کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10750234 | 1050296 | 2015 | 6 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Identification of ponatinib and other known kinase inhibitors with potent MEKK2 inhibitory activity
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کلمات کلیدی
EGFMEKK2FDAponatinibADPSARDMSO - DMSOMAPK - MAPKAdenosine Triphosphate - آدنوزین تری فسفاتATP - آدنوزین تری فسفات یا ATPadenosine diphosphate - آدنوزین دی فسفاتstandard deviation - انحراف معیارInhibitor - بازدارندهDimethyl sulfoxide - دیمتیل سولفواکسیدStructure-activity relationship - رابطه ساختار-فعالیتFood and Drug Administration - سازمان غذا و داروepidermal growth factor - عامل رشد اپیدرمیmitogen-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
![عکس صفحه اول مقاله: Identification of ponatinib and other known kinase inhibitors with potent MEKK2 inhibitory activity Identification of ponatinib and other known kinase inhibitors with potent MEKK2 inhibitory activity](/preview/png/10750234.png)
چکیده انگلیسی
The kinase MEKK2 (MAP3K2) may play an important role in tumor growth and metastasis for several cancer types. Thus, targeting MEKK2 may represent a novel strategy for developing more effective therapies for cancer. In order to identify small molecules with MEKK2 inhibitory activity, we screened a collection of known kinase inhibitors using a high throughput MEKK2 intrinsic ATPase enzyme assay and confirmed activity of the most potent hits with this primary assay. We also confirmed activities of these known kinase inhibitors with an MEKK2 transphosphorylation slot blot assay using MKK6 as a substrate. We observed a good correlation in potencies between the two orthogonal MEKK2 kinase activity assay formats for this set of inhibitors. We report that ponatinib, AT9283, AZD7762, JNJ-7706621, PP121 and hesperadin had potent MEKK2 enzyme inhibitory activities ranging from 4.7 to 60 nM IC50. Ponatinib is an FDA-approved drug that potently inhibited MEKK2 enzyme activity with IC50 values of 10-16 nM. AT9283 is currently in clinical trials and produced MEKK2 IC50 values of 4.7-18 nM. This set of known kinase inhibitors represents some of the most potent in vitro MEKK2 inhibitors reported to date and may be useful as research tools. Although these compounds are not selective for MEKK2, the structures of these compounds give insight into pharmacophores that potently inhibit MEKK2 and could be used as initial leads to design highly selective inhibitors of MEKK2.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical and Biophysical Research Communications - Volume 463, Issue 4, 7 August 2015, Pages 888-893
Journal: Biochemical and Biophysical Research Communications - Volume 463, Issue 4, 7 August 2015, Pages 888-893
نویسندگان
Syed Ahmad, Gary L. Johnson, John E. Scott,