Abbott Laboratories, Medicinal Chemistry, Worcester, Massachusetts 01605-2323, USA.
Expert Opin Ther Pat. 2009 Dec;19(12):1759-69. doi: 10.1517/13543770903397400.
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).
This review focuses on small molecules and summarizes the most recent TGF-betaR1 inhibitors reported in the patent literature.
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.
RESULTS/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.
TGF-β已被确定为多种疾病（尤其是癌症和纤维化）进展的关键因素。TGF-β信号可以通过三种不同策略进行调节：使用反义核苷酸阻断 TGF-β mRNA（trabedersen（AP 12009）），使用单克隆抗体阻断 TGF-β 同工型（lerdelimumab、metelimumab），或使用 TGF-β 受体 1（TGF-βR1 或 ALK-5）的小分子抑制剂。
本综述重点介绍小分子，并总结专利文献中报道的最新 TGF-βR1 抑制剂。
我们从 2005 年 1 月 1 日至 2009 年 1 月 1 日搜索并分析了主张 TGF-βR1 抑制作用的专利文献中的化学物质。
结果/结论：TGF-β 的抑制作用最近已通过反义核苷酸 trabedersen 在临床上得到验证。目前处于 I 期临床试验和临床前阶段的 TGF-βR1 小分子抑制剂具有很高的研究价值，通过口服给药可能提供更灵活的 TGF-β 调节途径，同时保持相同的治疗益处。
