Identification of a peptide inhibitor for the histone methyltransferase WHSC1

Morrison, Michael J.; Boriack-Sjodin, P. Ann; Swinger, Kerren K.; Wigle, Tim J.; Sadalge, Dipti; Kuntz, Kevin W.; Scott, Margaret Porter; Janzen, William P.; Chesworth, Richard; Duncan, Kenneth W.; Harvey, Darren M.; Lampe, John W.; Mitchell, Lorna H.; Copeland, Robert A.; Jeltsch, Albert

doi:10.1371/journal.pone.0197082

Title: Identification of a peptide inhibitor for the histone methyltransferase WHSC1

Journal Article · Wed May 09 00:00:00 EDT 2018 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0197082· OSTI ID:1466056

^[1]; Boriack-Sjodin, P. Ann ^[1]; Swinger, Kerren K. ^[1]; Wigle, Tim J. ^[1]; Sadalge, Dipti ^[1]; Kuntz, Kevin W. ^[1]; Scott, Margaret Porter ^[1]; Janzen, William P. ^[1]; Chesworth, Richard ^[1]; Duncan, Kenneth W. ^[1]; Harvey, Darren M. ^[1]; Lampe, John W. ^[1]; Mitchell, Lorna H. ^[1]; Copeland, Robert A. ^[1]; Jeltsch, Albert ^[2]

Epizyme Inc., Cambridge, MA (United States)
Univ. Stuttgart (Germany)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Epizyme, Inc

OSTI ID:: 1466056

Journal Information:: PLoS ONE, Vol. 13, Issue 5; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 15 works

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59 BASIC BIOLOGICAL SCIENCES
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lysine
enzyme inhibitors
enzymes
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Title: Identification of a peptide inhibitor for the histone methyltransferase WHSC1

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