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Title: Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8

Abstract

SETD8 is a histone H4–K20 methyltransferase that plays an essential role in the maintenance of genomic integrity during mitosis and in DNA damage repair, making it an intriguing target for cancer research. While some small molecule inhibitors for SETD8 have been reported, the structural binding modes for these inhibitors have not been revealed. Using the complex structure of the substrate peptide bound to SETD8 as a starting point, different natural and unnatural amino acid substitutions were tested, and a potent (Ki 50 nM, IC50 0.33 μM) and selective norleucine containing peptide inhibitor has been obtained.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [2];  [2];  [1];  [1];  [1]
  1. AbbVie Inc., Chicago, IL (United States)
  2. Univ. of Toronto, ON (Canada)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1397281
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
ACS Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 7; Journal Issue: 12; Journal ID: ISSN 1948-5875
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; SETD8; HMT; drug design; structure-based drug design; cancer

Citation Formats

Judge, Russell A., Zhu, Haizhong, Upadhyay, Anup K., Bodelle, Pierre M., Hutchins, Charles W., Torrent, Maricel, Marin, Violeta L., Yu, Wenyu, Vedadi, Masoud, Li, Fengling, Brown, Peter J., Pappano, William N., Sun, Chaohong, and Petros, Andrew M. Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8. United States: N. p., 2016. Web. doi:10.1021/acsmedchemlett.6b00303.
Judge, Russell A., Zhu, Haizhong, Upadhyay, Anup K., Bodelle, Pierre M., Hutchins, Charles W., Torrent, Maricel, Marin, Violeta L., Yu, Wenyu, Vedadi, Masoud, Li, Fengling, Brown, Peter J., Pappano, William N., Sun, Chaohong, & Petros, Andrew M. Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8. United States. https://doi.org/10.1021/acsmedchemlett.6b00303
Judge, Russell A., Zhu, Haizhong, Upadhyay, Anup K., Bodelle, Pierre M., Hutchins, Charles W., Torrent, Maricel, Marin, Violeta L., Yu, Wenyu, Vedadi, Masoud, Li, Fengling, Brown, Peter J., Pappano, William N., Sun, Chaohong, and Petros, Andrew M. 2016. "Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8". United States. https://doi.org/10.1021/acsmedchemlett.6b00303. https://www.osti.gov/servlets/purl/1397281.
@article{osti_1397281,
title = {Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8},
author = {Judge, Russell A. and Zhu, Haizhong and Upadhyay, Anup K. and Bodelle, Pierre M. and Hutchins, Charles W. and Torrent, Maricel and Marin, Violeta L. and Yu, Wenyu and Vedadi, Masoud and Li, Fengling and Brown, Peter J. and Pappano, William N. and Sun, Chaohong and Petros, Andrew M.},
abstractNote = {SETD8 is a histone H4–K20 methyltransferase that plays an essential role in the maintenance of genomic integrity during mitosis and in DNA damage repair, making it an intriguing target for cancer research. While some small molecule inhibitors for SETD8 have been reported, the structural binding modes for these inhibitors have not been revealed. Using the complex structure of the substrate peptide bound to SETD8 as a starting point, different natural and unnatural amino acid substitutions were tested, and a potent (Ki 50 nM, IC50 0.33 μM) and selective norleucine containing peptide inhibitor has been obtained.},
doi = {10.1021/acsmedchemlett.6b00303},
url = {https://www.osti.gov/biblio/1397281}, journal = {ACS Medicinal Chemistry Letters},
issn = {1948-5875},
number = 12,
volume = 7,
place = {United States},
year = {Fri Sep 30 00:00:00 EDT 2016},
month = {Fri Sep 30 00:00:00 EDT 2016}
}

Journal Article:
Free Publicly Available Full Text
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Cited by: 8 works
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Figures / Tables:

Figure 1 Figure 1: H4 peptide (16−23) areas of focus for design.

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Works referenced in this record:

Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase
journal, June 2005


Histone H4 Lysine 20 methylation: key player in epigenetic regulation of genomic integrity
journal, January 2013


Modulation of p53 Function by SET8-Mediated Methylation at Lysine 382
journal, August 2007


Histone Lysine Methyltransferase SETD8 Promotes Carcinogenesis by Deregulating PCNA Expression
journal, May 2012


SET8 Recognizes the Sequence RHRK 20 VLRDN within the N Terminus of Histone H4 and Mono-methylates Lysine 20
journal, June 2005


Small-Molecule Inhibitors of SETD8 with Cellular Activity
journal, September 2014


Identification of PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells
journal, November 2012


Discovery of a Selective, Substrate-Competitive Inhibitor of the Lysine Methyltransferase SETD8
journal, July 2014


Structure–activity relationship studies of SETD8 inhibitors
journal, January 2014


EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations
journal, October 2012


Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors
journal, January 2012


Discovery and Development of Potent and Selective Inhibitors of Histone Methyltransferase G9a
journal, January 2014


Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2
journal, May 2015


Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152)
journal, March 2012


Design and Synthesis of Statine-Based Cell-Permeable Peptidomimetic Inhibitors of Human β-Secretase
journal, April 2003


Constrained Peptides with Target-Adapted Cross-Links as Inhibitors of a Pathogenic Protein-Protein Interaction
journal, February 2014


A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers
journal, June 2012


Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide
journal, May 2016


Discovery of a Potent, Selective, and Cell-Active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6
journal, September 2016


Arginine Topology Controls Escape of Minimally Cationic Proteins from Early Endosomes to the Cytoplasm
journal, July 2012


Spontaneous Membrane-Translocating Peptides by Orthogonal High-Throughput Screening
journal, June 2011


Works referencing / citing this record:

Clinically Applicable Inhibitors Impacting Genome Stability
journal, May 2018


Identification of a peptide inhibitor for the histone methyltransferase WHSC1
journal, May 2018


Inhibitors of Protein Methyltransferases and Demethylases
journal, March 2017


Examining sterically demanding lysine analogs for histone lysine methyltransferase catalysis
journal, February 2020


Clinically Applicable Inhibitors Impacting Genome Stability
journal, May 2018


Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.