Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease.
Cell Chem Biol
; 24(8): 1029-1039.e7, 2017 Aug 17.
Article
in En
| MEDLINE
| ID: mdl-28820959
ABSTRACT
Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human disease. In certain cancers, TNF-α is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNF-α antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNF-α-mediated signaling. Here, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNF-α stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated and non-phosphorylated TAK1 that binds within the ATP-binding pocket and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNF-α-induced cell death, with general implications for cancer and autoimmune disease treatment.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Benzamides
/
Benzimidazoles
/
Tumor Necrosis Factor-alpha
/
MAP Kinase Kinase Kinases
/
Protein Kinase Inhibitors
Type of study:
Prognostic_studies
Limits:
Female
/
Humans
Language:
En
Journal:
Cell Chem Biol
Year:
2017
Document type:
Article
Affiliation country:
United States