<br>发现一种有效且选择性的 NSD2 靶向降解剂，用于还原 H3K36me2,Journal of the American Chemical Society

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发现一种有效且选择性的 NSD2 靶向降解剂，用于还原 H3K36me2
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-03-28 , DOI: 10.1021/jacs.3c01421
Ronan P Hanley ₁ , David Y Nie _{2,

3,

4} , John R Tabor ₁ , Fengling Li ₂ , Amin Sobh ₅ , Chenxi Xu _{6,

7} , Natalie K Barker ₈ , David Dilworth ₂ , Taraneh Hajian ₂ , Elisa Gibson ₂ , Magdalena M Szewczyk ₂ , Peter J Brown ₂ , Dalia Barsyte-Lovejoy _{2,

9} , Laura E Herring ₈ , Gang Greg Wang _{6,

7,

10} , Jonathan D Licht ₅ , Masoud Vedadi _{2,

9} , Cheryl H Arrowsmith _{2,

3,

4} , Lindsey I James _{1,

6}

Affiliation

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
University of Florida Health Cancer Center, The University of Florida Cancer and Genetics Research Complex, Gainesville, Florida 32610, United States.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.
UNC Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.

核受体结合 SET 结构域 2 (NSD2) 在基因调控中发挥重要作用，主要是通过其将组蛋白 3 (H3K36me2) 的赖氨酸 36 二甲基化的能力。尽管NSD2在多种癌症中存在异常活性，但迄今为止用小分子选择性抑制该蛋白催化活性的努力尚未成功。在这里，我们报告了 UNC8153 的开发，这是一种新型 NSD2 靶向降解剂，可有效、选择性地降低 NSD2 蛋白和 H3K36me2 染色质标记的细胞水平。 UNC8153 包含一个简单的弹头，可通过一种新颖的机制实现 NSD2 的蛋白酶体依赖性降解。重要的是，UNC8153通过降解NSD2介导的H3K36me2减少导致多发性骨髓瘤细胞中病理表型的下调，包括对含有激活点突变的MM1.S细胞的轻度抗增殖作用以及对含有t(4; 的KMS11细胞)的抗粘附作用。 14) 上调NSD2表达的易位。

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更新日期：2023-03-28

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