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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.
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
URL: https://doi.org/10.1016/j.bmc.2024.117597
DOI: 10.1016/j.bmc.2024.117597
Data Access Statement: Data will be made available on request.
PubMed id: 38262305
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