| Structure-based design of conformationally constrained cyclic peptidomimetics to target the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 methyltransferase activity |
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| 作者姓名： | Hacer Karatas Shirley Y. Lee Elizabeth C. Townsend Fang Cao Jing Xu Denzil Bernard Liu Liu Yali Dou Shaomeng Wang |
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| 作者单位： | a Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA;
b Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA;
c Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA;
d Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA;
e Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA |
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| 基金项目： | This work is supported by grants from the National Institutes of Health, USA (No. CA177307 to SW and YD), the Leukemia and Lymphoma Society (to SW and YD) and Stand Up to Cancer (to YD). |
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| 摘 要： | We described herein structure-based design,synthesis and evaluation of conformationally constrained,cyclic peptidomimetics to block the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 histone methyltransferase activity.Our study has yielded cyclic peptidomimetics with very high binding affinities to WDR5(Kivalues 1 nmol/L) and function as antagonists of the MLL1 histone methyltransferase activity.
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| 收稿时间： | 2015-01-23 |
| 修稿时间： | 2015-03-03 |
Structure-based design of conformationally constrained cyclic peptidomimetics to target the MLL1-WDR5 protein-protein interaction as inhibitors of the MLL1 methyltransferase activity |
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| Hacer Karatas,Shirley Y. Lee,Elizabeth C. Townsend,Fang Cao,Jing Xu,Denzil Bernard,Liu Liu,Yali Dou,Shaomeng Wang.Structure-based design of conformationally constrained cyclic peptidomimetics to target the MLL1-WDR5 protein-protein interaction as inhibitors of the MLL1 methyltransferase activity[J].Chinese Chemical Letters,2015,26(4):455-458. |
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| Authors: | Hacer Karatas Shirley Y Lee Elizabeth C Townsend Fang Cao Jing Xu Denzil Bernard Liu Liu Yali Dou Shaomeng Wang |
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| Institution: | a Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA;
b Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA;
c Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA;
d Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA;
e Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA |
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| Abstract: | We described herein structure-based design, synthesis and evaluation of conformationally constrained, cyclic peptidomimetics to block the MLL1-WDR5 protein-protein interaction as inhibitors of the MLL1 histone methyltransferase activity. Our study has yielded cyclic peptidomimetics with very high binding affinities to WDR5 (Ki values <1 nmol/L) and function as antagonists of the MLL1 histone methyltransferase activity. |
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| Keywords: | Epigenetics MLL1 histone methyltransferase WDR5-MLL1 interaction Small-molecule inhibitors Cyclic peptidomemtics |
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