Cyclic peptides target the aromatic cage of a PHD-finger reader domain to modulate epigenetic protein function

Author:

Coleman Oliver D.123ORCID,Macdonald Jessica2,Thomson Ben2,Ward Jennifer A.45,Stubbs Christopher J.6,McAllister Tom E.123ORCID,Clark Shane2,Amin Siddique1ORCID,Cao Yimang2,Abboud Martine I.2ORCID,Zhang Yijia2,Sanganee Hitesh7,Huber Kilian V. M.45ORCID,Claridge Tim D. W.2ORCID,Kawamura Akane123ORCID

Affiliation:

1. School of Natural and Environmental Sciences - Chemistry, Newcastle University, Newcastle, NE1 7RU, UK

2. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK

3. Radcliffe Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Old Road Campus, Oxford, OX3 7BN, UK

4. Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford OX3 7FZ, UK

5. Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK

6. Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, CB4 0WG, UK

7. Emerging Innovations Unit, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK

Abstract

We report the development of a potent and selective de novo cyclic peptide ligand for epigenetic methyllysine reader domain. The cyclic peptide binds at the aromatic cage of PHD-finger and modulates the JmjC lysine demethylase activity of KDM7.

Funder

Cancer Research UK

Engineering and Physical Sciences Research Council

Myeloma UK

H2020 European Research Council

Publisher

Royal Society of Chemistry (RSC)

Subject

General Chemistry

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