Citation: 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. doi: 10.1016/j.cclet.2015.03.030 shu

Structure-based design of conformationally constrained cyclic peptidomimetics to target the MLL1-WDR5 protein-protein interaction as inhibitors of the MLL1 methyltransferase activity

Hacer Karatas ^a,b,c ,
Shirley Y. Lee ^d ,
Elizabeth C. Townsend ^d ,
Fang Cao ^d ,
Jing Xu ^d ,
Denzil Bernard ^b,c ,
Liu Liu ^b,c ,
Yali Dou ^d ,
Shaomeng Wang ^a,b,c,e,,

1.
a Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA;
2.
b Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA;
3.
c Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA;
4.
d Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA;
5.
e Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA

Corresponding author: Shaomeng Wang,
Received Date: 23 January 2015
Available Online: 3 March 2015
Fund Project:

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 (K_i values <1 nmol/L) and function as antagonists of the MLL1 histone methyltransferase activity.
- Epigenetics,
- MLL1 histone methyltransferase,
- WDR5-MLL1 interaction,
- Small-molecule inhibitors,
- Cyclic peptidomemtics
1. [1]
  [1] R. Marmorstein, Protein modules that manipulate histone tails for chromatin regulation, Nat. Rev. Mol. Cell Biol. 2 (2001) 422-432.
2. [2]
  [2] T. Kouzarides, Chromatin modifications and their function, Cell 128 (2007) 693-705.
3. [3]
  [3] G.G. Wang, C.D. Allis, P. Chi, Chromatin remodeling and cancer. Part I: Covalent histone modifications, Trends Mol. Med. 13 (2007) 363-372.
4. [4]
  [4] P. Chi, C.D. Allis, G.G. Wang, Covalent histone modifications-miswritten, misinterpreted and mis-erased in human cancers, Nat. Rev. Cancer 10 (2010) 457-469.
5. [5]
  [5] J.L. Hess, MLL: a histone methyltransferase disrupted in leukemia, Trends Mol. Med. 10 (2004) 500-507.
6. [6]
  [6] C.D. Jude, L. Climer, D. Xu, et al., Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors, Cell Stem Cell 1 (2007) 324-337.
7. [7]
  [7] F. Cao, E.C. Townsend, H. Karatas, et al., Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia, Mol. Cell 53 (2014) 247-261.
8. [8]
  [8] H. Karatas, E.C. Townsend, D. Bernard, Y. Dou, S. Wang, Analysis of the binding of mixed lineage leukemia 1 (MLL1) and histone 3 peptides to WD repeat domain 5 (WDR5) for the design of inhibitors of the MLL1-WDR5 interaction, J. Med. Chem. 53 (2010) 5179-5185.
9. [9]
  [9] H. Karatas, E.C. Townsend, F. Cao, et al., High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction, J. Am. Chem. Soc. 135 (2013) 669-682.
10. [10]
  [10] F. Cao, Y. Chen, T. Cierpicki, et al., An Ash2L/RbBP5 heterodimer stimulates the MLL1 methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain, PLoS ONE 5 (2010) e14102.
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沈阳化工大学材料科学与工程学院沈阳 110142