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. 2016 Oct 11;7(12):1102-1106.
doi: 10.1021/acsmedchemlett.6b00303. eCollection 2016 Dec 8.

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

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

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

Russell A Judge et al. ACS Med Chem Lett. .

Abstract

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.

Keywords: HMT; SETD8; cancer; drug design; structure-based drug design.

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Conflict of interest statement

The authors declare the following competing financial interest(s): The Structural Genomics Consortium (authors W.Y., M.V., F.L., and P.J.B.) is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA), Janssen, Merck & Co., Novartis Pharma AG, Pfizer, So Paulo Research Foundation-FAPESP, Takeda, and Wellcome Trust. R.A.J., H.Z., A.K.U., P.M.B., C.W.H., M.T., V.L.M., W.N.P., C.S., and A.M.P. are employees of AbbVie. The design, study conduct, and financial support for the research of these authors were provided by AbbVie. AbbVie participated in the interpretation of the data, review, and approval of the publication.

Figures

Figure 1
Figure 1
H4 peptide (16–23) areas of focus for design.
Figure 2
Figure 2
Overlay of the norleucine substituted peptide (2) complex structure (light blue, PDB ID: 5TEG) and the native H4 peptide complex structure (green, PDB ID: 1ZKK(2)). Residues from SETD8 forming the lysine channel are highlighted as sticks against the background of SETD8 shown as a cartoon. SAM/SAH, respectively, is shown as sticks at the top left. Figure prepared using PyMOL.
Figure 3
Figure 3
SETD8 activity with the norleucine substituted peptide (2), listed as Nle peptide in this figure, competing against the native H4 peptide (1–24). Experiments were performed in triplicate.
Figure 4
Figure 4
Selectivity of the norleucine substituted peptide (2) against a panel of 32 methyltransferases. Experiments performed in duplicate with average presented. Average estimated error ±4% inhibition. Peptide concentration, blue 1 μM, red 10 μM, and green 30 μM.
See this image and copyright information in PMC

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