Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5

Dong Dong Li; Wei Lin Chen; Xiao Li Xu; Fen Jiang; Lei Wang; Yi Yue Xie; Xiao Jin Zhang; Xiao Ke Guo; Qi Dong You; Hao Peng Sun

doi:10.1016/j.ejmech.2016.04.032

Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5

Dong Dong Li, Wei Lin Chen, Xiao Li Xu, Fen Jiang, Lei Wang, Yi Yue Xie, Xiao Jin Zhang, Xiao Ke Guo, Qi Dong You, Hao Peng Sun

Research output: Contribution to journal › Article › Research › peer-review

31 Citations (Scopus)

Abstract

MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC₅₀ = 0.3 μM) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC₅₀ = 104 nM) was the most potent small molecular, and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds.

Original language	English
Pages (from-to)	1-8
Number of pages	8
Journal	European Journal of Medicinal Chemistry
Volume	118
DOIs	https://doi.org/10.1016/j.ejmech.2016.04.032
Publication status	Published - 8 Aug 2016
Externally published	Yes

Keywords

Histone methyltransfreases
Leukemia
MLL1-WDR5 interaction
Small molecular inhibitors

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10.1016/j.ejmech.2016.04.032Licence: CC BY

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title = "Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5",

abstract = "MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC50 = 0.3 μM) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC50 = 104 nM) was the most potent small molecular, and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds.",

keywords = "Histone methyltransfreases, Leukemia, MLL1-WDR5 interaction, Small molecular inhibitors",

author = "Li, {Dong Dong} and Chen, {Wei Lin} and Xu, {Xiao Li} and Fen Jiang and Lei Wang and Xie, {Yi Yue} and Zhang, {Xiao Jin} and Guo, {Xiao Ke} and You, {Qi Dong} and Sun, {Hao Peng}",

note = "Funding Information: This work was supported by the project 81230078 (key program), 81202463 (youth foundation) and 91129732 of National Natural Science Foundation of China , Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. JKGQ201103 ), 2012AA020301 of 863 program, 2010ZX09401-401 , 2009ZX09501-003 and 2014ZX09507002-005-015 of the National Major Science and Technology Project of China (Innovation and Development of New Drugs) , Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP , 20130096110002 ). The authors declare no other conflicts of interest. Publisher Copyright: {\textcopyright} 2016 Elsevier Masson SAS.",

year = "2016",

month = aug,

day = "8",

doi = "10.1016/j.ejmech.2016.04.032",

language = "English",

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journal = "European Journal of Medicinal Chemistry",

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T1 - Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5

AU - Li, Dong Dong

AU - Chen, Wei Lin

AU - Xu, Xiao Li

AU - Jiang, Fen

AU - Wang, Lei

AU - Xie, Yi Yue

AU - Zhang, Xiao Jin

AU - Guo, Xiao Ke

AU - You, Qi Dong

AU - Sun, Hao Peng

N1 - Funding Information: This work was supported by the project 81230078 (key program), 81202463 (youth foundation) and 91129732 of National Natural Science Foundation of China , Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. JKGQ201103 ), 2012AA020301 of 863 program, 2010ZX09401-401 , 2009ZX09501-003 and 2014ZX09507002-005-015 of the National Major Science and Technology Project of China (Innovation and Development of New Drugs) , Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP , 20130096110002 ). The authors declare no other conflicts of interest. Publisher Copyright: © 2016 Elsevier Masson SAS.

PY - 2016/8/8

Y1 - 2016/8/8

N2 - MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC50 = 0.3 μM) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC50 = 104 nM) was the most potent small molecular, and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds.

AB - MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC50 = 0.3 μM) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC50 = 104 nM) was the most potent small molecular, and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds.

KW - Histone methyltransfreases

KW - Leukemia

KW - MLL1-WDR5 interaction

KW - Small molecular inhibitors

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ER -

Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5

Abstract

Keywords

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