Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders

被引：42

作者：

Doelle, Anja ^{[1
]}

Adhikari, Bikash ^{[3
]}

Kraemer, Andreas ^{[1
,2
]}

Weckesser, Janik ^{[1
,2
]}

Berner, Nicola ^{[4
,5
]}

Berger, Lena-Marie ^{[1
,2
]}

Diebold, Mathias ^{[6
]}

Szewczyk, Magdalena M. ^{[7
]}

Barsyte-Lovejoy, Dalia ^{[7
,8
]}

Arrowsmith, Cheryl H. ^{[7
,9
,10
]}

Gebel, Jakob ^{[1
,11
,12
,13
]}

Loehr, Frank ^{[1
,11
,12
,13
]}

Doetsch, Volker ^{[1
,10
]}

Eilers, Martin ^{[14
]}

Heinzlmeir, Stephanie ^{[4
]}

Kuster, Bernhard ^{[4
,5
,15
]}

Sotriffer, Christoph ^{[6
]}

Wolf, Elmar ^{[16
]}

Knapp, Stefan ^{[1
,2
,5
]}

机构：

[1] Goethe Univ Frankfurt Main, Buchmann Inst Life Sci BMLS, Struct Genom Consortium SGC, D-60438 Frankfurt, Germany

[2] Goethe Univ Frankfurt Main, Inst Pharmazeut Chem, D-60438 Frankfurt, Germany

[3] Univ Wurzburg, Theodor Boveri Inst, Canc Syst Biol Grp, D-97074 Wurzburg, Germany

[4] Tech Univ Munich, Chair Prote & Bioanalyt, D-85354 Freising Weihenstephan, Germany

[5] German Canc Res Ctr, German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[6] Univ Wurzburg, Inst Pharm & Lebensmittelchem, D-97074 Wurzburg, Germany

[7] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

[8] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5G 2M9, Canada

[9] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2C1, Canada

[10] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada

[11] Goethe Univ Frankfurt Main, Inst Biophys Chem, D-60438 Frankfurt, Germany

[12] Goethe Univ Frankfurt Main, Ctr Biomol Magnet Resonance, D-60438 Frankfurt, Germany

[13] Goethe Univ Frankfurt Main, Cluster Excellence Macromol Complexes CEF, D-60438 Frankfurt, Germany

[14] Univ Wurzburg, Theodor Boveri Inst, Dept Biochem & Mol Biol, D-97074 Wurzburg, Germany

[15] Tech Univ Munich, Bavarian Biomol Mass Spectrometry Ctr BayBioMS, D-85354 Freising Weihenstephan, Germany

[16] Univ Warzburg, Theodor Boveri Inst, Canc Syst Biol Grp, D-97074 Wurzburg, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 15期

基金：

加拿大创新基金会; 巴西圣保罗研究基金会; 欧洲研究理事会;

关键词：

E3 UBIQUITIN LIGASE; TRANSCRIPTION FACTORS; GENE-EXPRESSION; SMALL MOLECULES; C-MYC; CANCER; METHYLATION; OPTIMIZATION; CHROMATIN; DYNAMICS;

D O I：

10.1021/acs.jmedchem.1c00146

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Histone H3K4 methylation serves as a post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferase (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat-containing protein 5 (WDR5) that has also been associated with controlling long noncoding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMT complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic functions. This study presents the design, synthesis, and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.

引用

页码：10682 / 10710

页数：29

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