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

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.

doi:10.1021/acsmedchemlett.6b00303

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

Journal Article · Fri Sep 30 00:00:00 EDT 2016 · ACS Medicinal Chemistry Letters

DOI:https://doi.org/10.1021/acsmedchemlett.6b00303· OSTI ID:1397281

Judge, Russell A. ^[1]; Zhu, Haizhong ^[1]; Upadhyay, Anup K. ^[1]; Bodelle, Pierre M. ^[1]; Hutchins, Charles W. ^[1]; Torrent, Maricel ^[1]; Marin, Violeta L. ^[1]; Yu, Wenyu ^[2]; Vedadi, Masoud ^[2]; Li, Fengling ^[2]; Brown, Peter J. ^[2]; Pappano, William N. ^[1]; Sun, Chaohong ^[1]; Petros, Andrew M. ^[1]

AbbVie Inc., Chicago, IL (United States)
Univ. of Toronto, ON (Canada)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1397281

Journal Information:: ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 12 Vol. 7; ISSN 1948-5875

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Examining sterically demanding lysine analogs for histone lysine methyltransferase catalysis Temimi, Abbas H. K. Al; Tran, Vu; Teeuwen, Ruben S. Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-60337-3	journal	February 2020
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