Abstract
WHSC1 is a histone methyltransferase that is responsible for mono- and dimethylation of lysine 36 on histone H3 and has been implicated as a driver in a variety of hematological and solid tumors. Currently, there is a complete lack of validated chemical matter for this important drug discovery target. Herein we report on the first fully validated WHSC1 inhibitor, PTD2, a norleucine-containing peptide derived from the histone H4 sequence. This peptide exhibits micromolar affinity towards WHSC1 in biochemical and biophysical assays. Furthermore, a crystal structure was solved with the peptide in complex with SAM and the SET domain of WHSC1L1. This inhibitor is an important first step in creating potent, selective WHSC1 tool compounds for the purposes of understanding the complex biology in relation to human disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
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Histone-Lysine N-Methyltransferase / chemistry
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Histone-Lysine N-Methyltransferase / genetics
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Histones / chemistry
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Histones / genetics
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Humans
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Lysine / chemistry
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Neoplasms / drug therapy*
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Neoplasms / enzymology
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Norleucine / analogs & derivatives
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Norleucine / chemistry
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Norleucine / pharmacology
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PR-SET Domains / genetics
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Peptides / chemistry*
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Peptides / genetics
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Protein Conformation / drug effects
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Repressor Proteins / antagonists & inhibitors*
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Repressor Proteins / chemistry
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Repressor Proteins / genetics
Substances
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Enzyme Inhibitors
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Histones
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Peptides
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Repressor Proteins
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Norleucine
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Histone-Lysine N-Methyltransferase
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NSD2 protein, human
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Lysine
Grants and funding
This work was funded by Epizyme, Inc. The funding entities had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.