Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8
Journal Article
·
· ACS Medicinal Chemistry Letters
- 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.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC)
- Grant/Contract Number:
- AC02-06CH11357
- OSTI ID:
- 1397281
- Journal Information:
- ACS Medicinal Chemistry Letters, Vol. 7, Issue 12; ISSN 1948-5875
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Cited by: 8 works
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