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:
-
- AbbVie Inc., Chicago, IL (United States)
- 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}
}
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Cited by: 8 works
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Figures / Tables:
Figure 1: H4 peptide (16−23) areas of focus for design.
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Works referenced in this record:
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Works referencing / citing this record:
The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review
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Clinically Applicable Inhibitors Impacting Genome Stability
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Identification of a peptide inhibitor for the histone methyltransferase WHSC1
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BindingDB Entry 50048027: Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8.
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Inhibitors of Protein Methyltransferases and Demethylases
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Clinically Applicable Inhibitors Impacting Genome Stability
journal, May 2018
- Prakash, Anu; Garcia-Moreno, Juan; Brown, James
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Figures / Tables found in this record:
Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.