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ACS Med Chem Lett. 2016 Oct 11;7(12):1102-1106. eCollection 2016 Dec 8.

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

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AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Structural Genomics Consortium, University of Toronto , 101 College Street, Toronto, ON M5G 1L7, 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.


HMT; SETD8; cancer; drug design; structure-based drug design

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