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

被引：0

作者：

Uguen, Melanie ^{[1
]}

Shell, Devan J. ^{[1
]}

Silva, Madhushika ^{[2
]}

Deng, Yu ^{[3
,4
]}

Li, Fengling ^{[2
]}

Szewczyk, Magdalena M. ^{[2
]}

Yang, Ka ^{[5
]}

Zhao, Yani ^{[1
]}

Stashko, Michael A. ^{[1
]}

Norris-Drouin, Jacqueline L. ^{[1
]}

Waybright, Jarod M. ^{[1
,7
]}

Beldar, Serap ^{[2
]}

Rectenwald, Justin M. ^{[1
]}

Mordant, Angie L. ^{[6
]}

Webb, Thomas S. ^{[6
]}

Herring, Laura E. ^{[6
]}

Arrowsmith, Cheryl H. ^{[2
]}

Ackloo, Suzanne ^{[2
]}

Gygi, Steven P. ^{[5
]}

Mcginty, Robert K. ^{[1
,3
,4
]}

Barsyte-Lovejoy, Dalia ^{[2
]}

Liu, Pengda ^{[3
,4
]}

Halabelian, Levon ^{[2
]}

James, Lindsey I. ^{[1
,3
]}

Pearce, Kenneth H. ^{[1
,3
]}

Frye, Stephen V. ^{[1
,3
]}

机构：

[1] Univ North Carolina Chapel Hill, Ctr Integrat Chem Biol & Drug Discovery, UNC Eshelman Sch Pharm, Chem Biol & Med Chem, Chapel Hill, NC 27599 USA

[2] Univ Toronto, Toronto, ON, Canada

[3] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA

[4] Univ North Carolina Chapel Hill, Dept Biochem & Biophys, Chapel Hill, NC USA

[5] Harvard Med Sch, Dept Cell Biol, Boston, MA USA

[6] Univ North Carolina Chapel Hill, Dept Pharmacol, UNC Metabol & Prote Core Facil, Chapel Hill, NC USA

[7] Design Therapeut, Carlsbad, CA USA

来源：

NATURE COMMUNICATIONS | 2025年 / 16卷 / 01期

基金：

加拿大健康研究院; 加拿大创新基金会; 加拿大自然科学与工程研究理事会; 美国国家卫生研究院;

关键词：

D O I：

10.1038/s41467-025-57005-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 x 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.

引用

页数：16

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