Potent and selective SETDB1 covalent negative allosteric modulator reduces methyltransferase activity in cells

Mélanie Uguen, Devan J. Shell, Madhushika Silva, Yu Deng, Fengling Li, Magdalena M. Szewczyk, Ka Yang, Yani Zhao, Michael A. Stashko, Jacqueline L. Norris-Drouin, Jarod M. Waybright, Serap Beldar, Justin M. Rectenwald, Angie L. Mordant, Thomas S. Webb, Laura E. Herring, Cheryl H. Arrowsmith, Suzanne Ackloo, Steven P. Gygi, Robert K. McGinty, Dalia Barsyte-Lovejoy, Pengda Liu, Levon Halabelian, Lindsey I. James, Kenneth H. Pearce and Stephen V. Frye ()
Additional contact information
Mélanie Uguen: University of North Carolina at Chapel Hill
Devan J. Shell: University of North Carolina at Chapel Hill
Madhushika Silva: University of Toronto
Yu Deng: University of North Carolina at Chapel Hill School of Medicine
Fengling Li: University of Toronto
Magdalena M. Szewczyk: University of Toronto
Ka Yang: Harvard Medical School
Yani Zhao: University of North Carolina at Chapel Hill
Michael A. Stashko: University of North Carolina at Chapel Hill
Jacqueline L. Norris-Drouin: University of North Carolina at Chapel Hill
Jarod M. Waybright: University of North Carolina at Chapel Hill
Serap Beldar: University of Toronto
Justin M. Rectenwald: University of North Carolina at Chapel Hill
Angie L. Mordant: University of North Carolina at Chapel Hill
Thomas S. Webb: University of North Carolina at Chapel Hill
Laura E. Herring: University of North Carolina at Chapel Hill
Cheryl H. Arrowsmith: University of Toronto
Suzanne Ackloo: University of Toronto
Steven P. Gygi: Harvard Medical School
Robert K. McGinty: University of North Carolina at Chapel Hill
Dalia Barsyte-Lovejoy: University of Toronto
Pengda Liu: University of North Carolina at Chapel Hill School of Medicine
Levon Halabelian: University of Toronto
Lindsey I. James: University of North Carolina at Chapel Hill
Kenneth H. Pearce: University of North Carolina at Chapel Hill
Stephen V. Frye: University of North Carolina at Chapel Hill

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract A promising drug target, SETDB1, is a dual methyl-lysine (Kme) reader and methyltransferase implicated in cancer and neurodegenerative disease progression. To help understand the role of the triple Tudor domain (3TD) of SETDB1, its Kme reader, we first identify a low micromolar potency small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization leads to the discovery of UNC10013, a covalent 3TD ligand targeting Cys385 of SETDB1. UNC10013 is potent with a kinact/KI of 1.0 × 106 M−1s−1 and demonstrates proteome-wide selectivity. In cells, negative allosteric modulation of SETDB1-mediated Akt methylation occurs after treatment with UNC10013. Therefore, UNC10013 is a potent, selective, and cell-active covalent ligand for the 3TD of SETDB1, demonstrating negative allosteric modulator properties and making it a promising tool to study the biological role of SETDB1 in disease progression.

Date: 2025
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DOI: 10.1038/s41467-025-57005-3

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