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

共 50 条

[31] Structure-Activity Relationship Study of Indole-2-carboxamides Identifies a Potent Allosteric Modulator for the Cannabinoid Receptor 1 (CB1)
Mahmoud, Mariam M.
Ai, Hamed I.
Ahn, Kwang H.
Damaraju, Aparna
Samala, Sushma
Pulipati, Venkata K.
Kolluru, Srikanth
Kendall, Debra A.
Lu, Dai
JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (20) : 7965 - 7975
[32] Discovery of LY3154207, a potent and selective dopamine receptor D1 positive allosteric modulator for the treatment of Parkinson's disease dementia
Hao, Junliang
Beck, James
Krushinski, Joseph
Schaus, John
Wang, Xu-shan
Heinz, Beverly
Bruns, Robert
Bender, David
Cramer, Jeffery
Svensson, Kjell
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2018, 256
[33] Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells
Hui, AM
Wei, Z
Wei, C
Xi, D
Purow, B
Friedman, GC
Fine, HA
CANCER RESEARCH, 2004, 64 (24) : 9115 - 9123
[34] Discovery of 4-arylquinoline-2-carboxamides, highly potent and selective class of mGluR2 negative allosteric modulators: From HTS to activity in animal models
Shu, Youheng
Diamond, Tracy L.
Hershey, James C.
Huang, Shaei
Magliaro, Brian C.
O'Brien, Julie A.
Schlegel, Kelly-Ann S.
Puri, Vanita
Uebele, Victor N.
Uslaner, Jason M.
Wang, Cheng
Converso, Antonella
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2020, 30 (09)
[35] Discovery and Characterization of 2-(Cyclopropanesulfonamido)-N-(2-ethoxyphenyl) benzamide, ML382: a Potent and Selective Positive Allosteric Modulator of MrgX1
Wen, Wandong
Wang, Yan
Li, Zhe
Tseng, Pang-Yen
McManus, Owen B.
Wu, Meng
Li, Min
Lindsley, Craig W.
Dong, Xinzhong
Hopkins, Corey R.
CHEMMEDCHEM, 2015, 10 (01) : 57 - 61
[36] CB1 CANNABINOID RECEPTOR NEGATIVE ALLOSTERIC MODULATOR BLOCKED ETHANOL-MEDIATED INCREASE IN NEUROIMMUNE GENE EXPRESSION IN NEURONAL AND MICROGLIAL CELLS
Vaidyanathan, M.
Sellah, N.
Mukhopadhyay, S.
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 2018, 42 : 25A - 25A
[37] RO7049389, a core protein allosteric modulator, is safe and well tolerated in healthy volunteers and demonstrates potent anti-HBV activity in a phase 1 trial
Gane, E.
Liu, A.
Yuen, M-F
Schwabe, C.
Bo, Q.
Das, S. K.
Gao, L.
Zhou, X.
Wang, Y.
Coakley, E.
Jin, Y.
JOURNAL OF VIRAL HEPATITIS, 2018, 25 : 46 - 47
[38] Discovery of a Potent and Selective Covalent Inhibitor and Activity-Based Probe for the Deubiquitylating Enzyme UCHL1, with Antifibrotic Activity (vol 142, pg 12020, 2020)
Panyain, Nattawadee
Godinat, Aurelien
Lanyon-Hogg, Thomas
Lachiondo-Ortega, Sofia
Will, Edward J.
Soudy, Christelle
Mondal, Milon
Mason, Katie
Elkhalifa, Sarah
Smith, Lisa M.
Harrigan, Jeanine A.
Tate, Edward W.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2020, 142 (35) : 15199 - 15199
[39] Cenerimod, a Potent, Selective and Orally Active Sphingosine 1-phosphate Receptor 1 Modulator, Reduced Blood Antibody-secreting Cells in Patients with SLE
Strasser, Daniel
Sippel, Virginie
Grieder, Ursula
Kieninger-Graefitsch, Andrea
Pierlot, Gabin
Farine, Herve
Kulig, Paulina
Bourquin, Geoffroy
Keller, Marcel
Groenen, Peter
Trendelenburg, Marten
Murphy, Mark
ARTHRITIS & RHEUMATOLOGY, 2019, 71
[40] N-Acyl-N′-arylpiperazines as negative allosteric modulators of mGlu1: Identification of VU0469650, a potent and selective tool compound with CNS exposure in rats
Lovell, Kimberly M.
Felts, Andrew S.
Rodriguez, Alice L.
Venable, Daryl F.
Cho, Hyekyung P.
Morrison, Ryan D.
Byers, Frank W.
Daniels, J. Scott
Niswender, Colleen M.
Conn, P. Jeffrey
Lindsley, Craig W.
Emmitte, Kyle A.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (13) : 3713 - 3718

← 1 2 3 4 5 →