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Title: Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)–Mixed Lineage Leukemia (MLL) Protein–Protein Interaction

Abstract

We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5–mixed lineage leukemia (MLL) protein–protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC50 value of 0.90 nM (Ki value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC50 value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis for their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5–MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NCINIHOTHER
OSTI Identifier:
1374628
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 60; Journal Issue: 12
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Karatas, Hacer, Li, Yangbing, Liu, Liu, Ji, Jiao, Lee, Shirley, Chen, Yong, Yang, Jiuling, Huang, Liyue, Bernard, Denzil, Xu, Jing, Townsend, Elizabeth C., Cao, Fang, Ran, Xu, Li, Xiaoqin, Wen, Bo, Sun, Duxin, Stuckey, Jeanne A., Lei, Ming, Dou, Yali, and Wang, Shaomeng. Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)–Mixed Lineage Leukemia (MLL) Protein–Protein Interaction. United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.6b01796.
Karatas, Hacer, Li, Yangbing, Liu, Liu, Ji, Jiao, Lee, Shirley, Chen, Yong, Yang, Jiuling, Huang, Liyue, Bernard, Denzil, Xu, Jing, Townsend, Elizabeth C., Cao, Fang, Ran, Xu, Li, Xiaoqin, Wen, Bo, Sun, Duxin, Stuckey, Jeanne A., Lei, Ming, Dou, Yali, & Wang, Shaomeng. Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)–Mixed Lineage Leukemia (MLL) Protein–Protein Interaction. United States. doi:10.1021/acs.jmedchem.6b01796.
Karatas, Hacer, Li, Yangbing, Liu, Liu, Ji, Jiao, Lee, Shirley, Chen, Yong, Yang, Jiuling, Huang, Liyue, Bernard, Denzil, Xu, Jing, Townsend, Elizabeth C., Cao, Fang, Ran, Xu, Li, Xiaoqin, Wen, Bo, Sun, Duxin, Stuckey, Jeanne A., Lei, Ming, Dou, Yali, and Wang, Shaomeng. Tue . "Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)–Mixed Lineage Leukemia (MLL) Protein–Protein Interaction". United States. doi:10.1021/acs.jmedchem.6b01796.
@article{osti_1374628,
title = {Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)–Mixed Lineage Leukemia (MLL) Protein–Protein Interaction},
author = {Karatas, Hacer and Li, Yangbing and Liu, Liu and Ji, Jiao and Lee, Shirley and Chen, Yong and Yang, Jiuling and Huang, Liyue and Bernard, Denzil and Xu, Jing and Townsend, Elizabeth C. and Cao, Fang and Ran, Xu and Li, Xiaoqin and Wen, Bo and Sun, Duxin and Stuckey, Jeanne A. and Lei, Ming and Dou, Yali and Wang, Shaomeng},
abstractNote = {We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5–mixed lineage leukemia (MLL) protein–protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC50 value of 0.90 nM (Ki value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC50 value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis for their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5–MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.},
doi = {10.1021/acs.jmedchem.6b01796},
journal = {Journal of Medicinal Chemistry},
number = 12,
volume = 60,
place = {United States},
year = {Tue Jun 06 00:00:00 EDT 2017},
month = {Tue Jun 06 00:00:00 EDT 2017}
}