Optimization of a Class of Dihydrobenzofurane Analogs toward Orally Efficacious YAP-TEAD Protein-Protein Interaction Inhibitors

被引：11

作者：

Sellner, Holger ^{[1
]}

Chapeau, Emilie ^{[2
]}

Furet, Pascal ^{[1
]}

Voegtle, Markus ^{[1
]}

Salem, Bahaa ^{[1
]}

Le Douget, Mickael ^{[1
]}

Bordas, Vincent ^{[1
]}

Groell, Jean-Marc ^{[1
]}

Le Goff, Anne-Laure ^{[1
]}

Rouzet, Christine ^{[1
]}

Wietlisbach, Thomas ^{[1
]}

Zimmermann, Thomas ^{[1
]}

McKenna, Joseph ^{[1
]}

Brocklehurst, Cara E. E. ^{[1
]}

Chene, Patrick ^{[2
]}

Wartmann, Markus ^{[2
]}

Scheufler, Clemens ^{[3
]}

Kallen, Joerg ^{[3
]}

Williams, Gareth ^{[4
]}

Harlfinger, Stephanie ^{[4
]}

Traebert, Martin ^{[5
]}

Dumotier, Berengere M. ^{[5
]}

Schmelzle, Tobias ^{[2
]}

Soldermann, Nicolas ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Global Discovery Chem, CH-4002 Basel, Switzerland

[2] Novartis Inst Biomed Res, Oncol Drug Discovery, CH-4002 Basel, Switzerland

[3] Novartis Inst Biomed Res, Chem Biol & Therapeut, CH-4002 Basel, Switzerland

[4] Novartis Inst Biomed Res, Pharmacokinet Sci, CH-4002 Basel, Switzerland

[5] Novartis Inst Biomed Res, Preclin Safety, CH-4002 Basel, Switzerland

来源：

CHEMMEDCHEM | 2023年 / 18卷 / 11期

关键词：

TEAD; YAP; PPI inhibitors; multi-parameter optimization; in vivo efficacy; HIPPO PATHWAY;

D O I：

10.1002/cmdc.202300051

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the O-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time.

引用

页数：23

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