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.
1. [1]
  Tian Feng , Yun-Ling Gao , Di Hu , Ke-Yu Yuan , Shu-Yi Gu , Yao-Hua Gu , Si-Yu Yu , Jun Xiong , Yu-Qi Feng , Jie Wang , Bi-Feng Yuan . Chronic sleep deprivation induces alterations in DNA and RNA modifications by liquid chromatography-mass spectrometry analysis. Chinese Chemical Letters, 2024, 35(8): 109259-. doi: 10.1016/j.cclet.2023.109259
2. [2]
  Shu-Yi Gu , Tian Feng , Fang-Yin Gang , Si-Yu Yu , Wan Chan , Zhao-Cheng Ma , Yao-Hua Gu , Bi-Feng Yuan . Persistent organic pollutant perfluorooctanoic acid induces alterations in epigenetic modifications of DNA and RNA. Chinese Chemical Letters, 2025, 36(12): 110957-. doi: 10.1016/j.cclet.2025.110957
3. [3]
  Huiju Cao , Lei Shi . sp¹-Hybridized linear and cyclic carbon chain. Chinese Chemical Letters, 2025, 36(4): 110466-. doi: 10.1016/j.cclet.2024.110466
4. [4]
  Junliang Zhou , Tian-Bing Ren , Lin Yuan . The strategy to improve the brightness of organic small-molecule fluorescent dyes for imaging. Chinese Chemical Letters, 2025, 36(8): 110644-. doi: 10.1016/j.cclet.2024.110644
5. [5]
  Aolei Tan , Xiaoxiao Ma . Exploring the functional roles of small-molecule metabolites in disease research: Recent advancements in metabolomics. Chinese Chemical Letters, 2024, 35(8): 109276-. doi: 10.1016/j.cclet.2023.109276
6. [6]
  Qingyuan Guo , Aojie Liu , Yinghui Huang , Jiayu Ding , Junjie Ding , Limin Wang , Yang Ding , Bo Peng , Lin Li , Bin Fang , Shan Jiang , Hua Bai . Small-molecule fluorescent probes for imaging and diagnosing ischemia-reperfusion injury. Chinese Chemical Letters, 2025, 36(12): 110943-. doi: 10.1016/j.cclet.2025.110943
7. [7]
  Wen Su , Siying Liu , Qingfu Zhang , Zhongyan Zhou , Na Wang , Lei Yue . Temperature-controlled electrospray ionization tandem mass spectrometry study on protein/small molecule interaction. Chinese Chemical Letters, 2025, 36(5): 110237-. doi: 10.1016/j.cclet.2024.110237
8. [8]
  Yunjie Dang , Yanru Feng , Xiao Chen , Chaoxing He , Shujie Wei , Dingyang Liu , Jinlong Qi , Huaxing Zhang , Shaokun Yang , Zhiyun Niu , Bai Xiang . Development of a multi-level pH-responsive lipid nanoplatform for efficient co-delivery of siRNA and small-molecule drugs in tumor treatment. Chinese Chemical Letters, 2024, 35(12): 109660-. doi: 10.1016/j.cclet.2024.109660
9. [9]
  Xiaohui Fu , Yanping Zhang , Juan Liao , Zhen-Hua Wang , Yong You , Jian-Qiang Zhao , Mingqiang Zhou , Wei-Cheng Yuan . Palladium-catalyzed enantioselective decarboxylation of vinyl cyclic carbamates: Generation of amide-based aza-1,3-dipoles and application to asymmetric 1,3-dipolar cycloaddition. Chinese Chemical Letters, 2024, 35(12): 109688-. doi: 10.1016/j.cclet.2024.109688
10. [10]
  Yuan Xiong , Lan-Hui Qin , Bei Zhao , Lei-Zhi Xu , Yu-Fan Fan , Tian Tian , Hai-Rong Zeng , Ting Liu , Jian Huang , Jian-Ming Sun , Zhen-Hao Tian , Guang-Bo Ge . Structure-based design and development of halogenated-naphthalimides as potent hCYP1B1 inhibitors for overcoming paclitaxel resistance. Chinese Chemical Letters, 2025, 36(11): 110812-. doi: 10.1016/j.cclet.2024.110812
11. [11]
  Shiqi Xu , Zi Ye , Shuang Shang , Fengge Wang , Huan Zhang , Lianguo Chen , Hao Lin , Chen Chen , Fang Hua , Chong-Jing Zhang . Pairs of thiol-substituted 1,2,4-triazole-based isomeric covalent inhibitors with tunable reactivity and selectivity. Chinese Chemical Letters, 2024, 35(7): 109034-. doi: 10.1016/j.cclet.2023.109034
12. [12]
  Yifan Feng , Chengjuan Chen , Anqi Shao , Qingyang Zhang , Lan Sun , Hai-Yu Hu , Tiantai Zhang . Recent advances in interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors and PROTACs. Chinese Chemical Letters, 2025, 36(12): 110963-. doi: 10.1016/j.cclet.2025.110963
13. [13]
  Ali Dai , Zhiguo Zheng , Liusheng Duan , Jian Wu , Weiming Tan . Small molecule chemical scaffolds in plant growth regulators for the development of agrochemicals. Chinese Chemical Letters, 2025, 36(4): 110462-. doi: 10.1016/j.cclet.2024.110462
14. [14]
  Yi-Ru Bai , Qing-Chuan Duan , Dong-Jie Seng , Ying Xu , Hong-Bo Ren , Jie Zhang , Dan-Dan Shen , Li Yang , Hong-Min Liu , Shuo Yuan . A comprehensive review of small molecule drugs approved by the FDA in 2024: Advance and prospect. Chinese Chemical Letters, 2025, 36(10): 111025-. doi: 10.1016/j.cclet.2025.111025
15. [15]
  Yulong Shi , Fenbei Chen , Mengyuan Wu , Xin Zhang , Runze Meng , Kun Wang , Yan Wang , Yuheng Mei , Qionglu Duan , Yinghong Li , Rongmei Gao , Yuhuan Li , Hongbin Deng , Jiandong Jiang , Yanxiang Wang , Danqing Song . Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1. Chinese Chemical Letters, 2024, 35(5): 108792-. doi: 10.1016/j.cclet.2023.108792
16. [16]
  Zhaoyong Kang , Shen Li , Yan Li , Jingfeng Song , Yangrui Peng , Yihua Chen . Small molecular inhibitors and degraders targeting STAT3 for cancer therapy: An updated review (from 2022 to 2024). Chinese Chemical Letters, 2025, 36(7): 110447-. doi: 10.1016/j.cclet.2024.110447
17. [17]
  Kun Zhang , Ni Dan , Dan-Dan Ren , Ruo-Yu Zhang , Xiaoyan Lu , Ya-Pan Wu , Li-Lei Zhang , Hong-Ru Fu , Dong-Sheng Li . A small D-A molecule with highly heat-resisting room temperature phosphorescence for white emission and anti-counterfeiting. Chinese Journal of Structural Chemistry, 2024, 43(3): 100244-100244. doi: 10.1016/j.cjsc.2024.100244
18. [18]
  Hyoseok Kim , Changyi Cui , Kohei Toh , Genyir Ado , Tetsuya Ogawa , Yixin Zhang , Shin-ichi Sato , Yong-Beom Lim , Hiroki Kurata , Lu Zhou , Motonari Uesugi . Discovery of a self-assembling small molecule that sequesters RNA-binding proteins. Chinese Chemical Letters, 2025, 36(5): 110135-. doi: 10.1016/j.cclet.2024.110135
19. [19]
  Jiawei Zhu , Yucheng Xiong , Xiaoxue Bai , Chenlong Xie , Baichen Xiong , Yao Chen , Haopeng Sun . Small molecule-drug conjugates: Mechanistic insights and strategic design for enhanced cancer therapy. Chinese Chemical Letters, 2025, 36(10): 110799-. doi: 10.1016/j.cclet.2024.110799
20. [20]
  An Lu , Yuhao Guo , Yi Yan , Lin Zhai , Xiangyu Wang , Weiran Cao , Zijie Li , Zhixia Zhao , Yujie Shi , Yuanjun Zhu , Xiaoyan Liu , Huining He , Zhiyu Wang , Jian-Cheng Wang . Nanomedicine integrating the lipidic derivative of 5-fluorouracil, miriplatin and PD-L1 siRNA for enhancing tumor therapy. Chinese Chemical Letters, 2024, 35(6): 108928-. doi: 10.1016/j.cclet.2023.108928

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(1033)
HTML views(7)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142