Natural Product Kongensin A is a Non-Canonical HSP90 Inhibitor that Blocks RIP3-dependent Necroptosis

Dianrong Li; Chao Li; Lin Li; She Chen; Lei Wang; Qiang Li; Xiaodong Wang; Xiaoguang Lei; Zhirong Shen

doi:10.1016/j.chembiol.2015.08.018

Natural Product Kongensin A is a Non-Canonical HSP90 Inhibitor that Blocks RIP3-dependent Necroptosis

Cell Chem Biol. 2016 Feb 18;23(2):257-266. doi: 10.1016/j.chembiol.2015.08.018. Epub 2016 Jan 28.

Authors

Dianrong Li¹, Chao Li², Lin Li³, She Chen³, Lei Wang³, Qiang Li³, Xiaodong Wang⁴, Xiaoguang Lei⁵, Zhirong Shen⁶

Affiliations

¹ Graduate Program, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
² Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
³ National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
⁴ National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China; Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.
⁵ National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China; Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: [email protected].
⁶ National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China; Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China. Electronic address: [email protected].

PMID: 27028885
DOI: 10.1016/j.chembiol.2015.08.018

Abstract

RIP3-dependent necroptosis has recently garnered significant interest because of the unique signaling mechanisms and pathologic functions involved in this process. Accordingly, a number of chemical screens have identified several effective small-molecule inhibitors that specifically block necroptosis. Here, we report the discovery that kongensin A (KA), a natural product isolated from Croton kongensis, is a potent inhibitor of necroptosis and an inducer of apoptosis. Using a new bioorthogonal ligation method (TQ ligation), we reveal that the direct cellular target of KA is heat shock protein 90 (HSP90). Further studies demonstrate that KA covalently binds to a previously uncharacterized cysteine 420 in the middle domain of HSP90 and dissociates HSP90 from its cochaperone CDC37, which leads to inhibition of RIP3-dependent necroptosis and promotion of apoptosis in multiple cancer cell lines. Collectively, our findings demonstrate that KA is an effective HSP90 inhibitor that has potential anti-necroptosis and anti-inflammation applications.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Phytogenic / chemistry
Antineoplastic Agents, Phytogenic / isolation & purification
Antineoplastic Agents, Phytogenic / pharmacology*
Apoptosis / drug effects*
Biological Products / chemistry
Biological Products / isolation & purification
Biological Products / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Croton / chemistry
Diterpenes / chemistry
Diterpenes / isolation & purification
Diterpenes / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
HT29 Cells
HeLa Cells
Humans
Necrosis / drug therapy
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / isolation & purification
Protein Kinase Inhibitors / pharmacology*
Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents, Phytogenic
Biological Products
Diterpenes
HSP90 Heat-Shock Proteins
HSP90AB1 protein, human
Protein Kinase Inhibitors
kongensin A
RIPK3 protein, human
Receptor-Interacting Protein Serine-Threonine Kinases