Development of a Covalent Inhibitor of c-Jun N-Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1

被引：16

作者：

Lu, Wenchao ^{[1
,2
,3
]}

Liu, Yao ^{[4
,5
]}

Gao, Yang ^{[4
,5
]}

Geng, Qixiang ^{[1
,2
]}

Gurbani, Deepak ^{[6
]}

Li, Lianbo ^{[6
]}

Ficarro, Scott B. ^{[7
]}

Meyer, Cynthia J. ^{[6
]}

Sinha, Dhiraj ^{[6
]}

You, Inchul ^{[1
,2
]}

Tse, Jason ^{[1
,2
]}

He, Zhixiang ^{[4
,5
]}

Ji, Wenzhi ^{[1
,2
]}

Che, Jianwei ^{[4
,5
]}

Kim, Audrey Y. ^{[1
,2
]}

Yu, Tengteng ^{[8
,9
,10
,11
,12
]}

Wen, Kenneth ^{[8
,9
,10
]}

Anderson, Kenneth C. ^{[8
,9
,10
]}

Marto, Jarrod A. ^{[7
,13
,14
]}

Westover, Kenneth D. ^{[6
]}

Zhang, Tinghu ^{[1
,2
]}

Gray, Nathanael S. ^{[1
,2
]}

机构：

[1] Stanford Univ, Chem H, Stanford Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA

[2] Stanford Univ, Stanford Canc Inst, Stanford Sch Med, Stanford, CA 94305 USA

[3] Lingang Lab, Shanghai 200031, Peoples R China

[4] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[5] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA

[6] Univ Texas Southwestern Med Ctr Dallas, Dept Radiat Oncol, Dept Biochem, Dallas, TX 75390 USA

[7] Dana Farber Canc Inst, Blais Prote Ctr, Ctr Emergent Drug Targets, Dept Canc Biol, Boston, MA 02215 USA

[8] Dana Farber Canc Inst, Jerome Lipper Myeloma Ctr, Dept Med Oncol, Boston, MA 02215 USA

[9] Dana Farber Canc Inst, Le Bow Inst Myeloma Therapeut, Boston, MA 02215 USA

[10] Dana Farber Canc Inst, Jerome Lipper Myeloma Ctr, Boston, MA 02215 USA

[11] Chinese Acad Med Sci & Peking Union Med Coll, Inst Hematol, State Key Lab Expt Hematol, Natl Clin Res Ctr Blood Dis,Haihe Lab Cell Ecosy, Tianjin 300020, Peoples R China

[12] Chinese Acad Med Sci & Peking Union Med Coll, Blood Dis Hosp, Tianjin 300020, Peoples R China

[13] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA

[14] Harvard Med Sch, Boston, MA 02215 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 05期

关键词：

DISCOVERY; DESIGN; PREDICTION; GENERATION; POTENT;

D O I：

10.1021/acs.jmedchem.2c01834

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family, which includes JNK1-JNK3. Interestingly, JNK1 and JNK2 show opposing functions, with JNK2 activity favoring cell survival and JNK1 stimulating apoptosis. Isoform-selective small molecule inhibitors of JNK1 or JNK2 would be useful as pharmacological probes but have been difficult to develop due to the similarity of their ATP binding pockets. Here, we describe the discovery of a covalent inhibitor YL5084, the first such inhibitor that displays selectivity for JNK2 over JNK1. We demonstrated that YL5084 forms a covalent bond with Cys116 of JNK2, exhibits a 20-fold higher K-inact/K-I compared to that of JNK1, and engages JNK2 in cells. However, YL5084 exhibited JNK2-independent antiproliferative effects in multiple myeloma cells, suggesting the existence of additional targets relevant in this context. Thus, although not fully optimized, YL5084 represents a useful chemical starting point for the future development of JNK2-selective chemical probes.

引用

页码：3356 / 3371

页数：16

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