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Selective targeting of human TET1 by cyclic peptide inhibitors: Insights from biochemical profiling

Lookup NU author(s): Klemensas Simelis, Dr Hilal SaracORCiD, Dr Tom McAllisterORCiD, Dr Roman Belle, Professor Akane Kawamura



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Ten-Eleven Translocation (TET) enzymes are Fe(II)/2OG-dependent oxygenases that play important roles in epigenetic regulation, but selective inhibition of the TETs is an unmet challenge. We describe the profiling of previously identified TET1-binding macrocyclic peptides. TiP1 is established as a potent TET1 inhibitor (IC50 = 0.26 µM) with excellent selectivity over other TETs and 2OG oxygenases. TiP1 alanine scanning reveals the critical roles of Trp10 and Glu11 residues for inhibition of TET isoenzymes. The results highlight the utility of the RaPID method to identify potent enzyme inhibitors with selectivity over closely related paralogues. The structure–activity relationship data generated herein may find utility in the development of chemical probes for the TETs.

Publication metadata

Author(s): Simelis K, Saraç H, Salah E, Nishio K, McAllister TE, Corner TP, Tumber A, Belle R, Schofield CJ, Suga H, Kawamura A

Publication type: Article

Publication status: Published

Journal: Bioorganic & Medicinal Chemistry

Year: 2024

Volume: 99

Print publication date: 01/02/2024

Online publication date: 12/01/2024

Acceptance date: 10/01/2024

Date deposited: 11/03/2024

ISSN (print): 0968-0896

ISSN (electronic): 1464-3391

Publisher: Elsevier


DOI: 10.1016/j.bmc.2024.117597

PubMed id: 38262305


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Funder referenceFunder name
Cancer Research UK [C8717/A28285, C5255/A18085]
EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine [EP/L015838/1]
European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme [679479, 101003111]