Strategies for TGF-beta modulation: a review of recent patents.
BACKGROUND
TGF-beta has been identified as a key factor in the progression of various diseases, in particular cancer and fibrosis. The signaling of TGF-beta can be modulated through three distinct strategies: using antisense nucleotides that block TGF-beta mRNA (trabedersen (AP 12009)), using monoclonal antibodies to block TGF-beta isoforms (lerdelimumab, metelimumab) or using small molecule inhibitors of the TGF-beta receptor 1 (TGF-betaR1 or ALK-5).


OBJECTIVE
This review focuses on small molecules and summarizes the most recent TGF-betaR1 inhibitors reported in the patent literature.


METHODS
We searched and analyzed the patent literature claiming chemical matter for TGF-betaR1 inhibition from the 1(st) of January 2005 to the 1(st) of January 2009.


CONCLUSIONS
The inhibition of TGF-beta has recently been clinically validated with antisense nucleotide trabedersen. Small molecules inhibitors of TGF-betaR1 that are now in Phase I clinical trials and in preclinical stage are, therefore, of high interest and could provide a more versatile route to TGF-beta modulation through oral dosing while maintaining the same therapeutic benefits.
Bonafoux
Dominique
D
Abbott Laboratories, Medicinal Chemistry, Worcester, Massachusetts 01605-2323, USA. dominique.bonafoux@abbott.com
Lee
Wen-Cherng
WC
D000818:Animals; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D010330:Patents as Topic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human