TGF-beta Inhibitor / TGF-beta Inhibitors

Misregulation of the activity of TGF-beta (Transforming Growth Factor-beta) family members is involved in pathogenesis of cancer, muscular dystrophy, obesity and bone and tooth remodeling. Natural inhibitors for the TGF-beta superfamily regulate fine-tuning of activity of TGF-beta family in vivo . In addition to natural inhibitors for the TGF-beta family, soluble forms of receptors for the TGF-beta family, blocking monoclonal antibodies and small chemical TGF-beta inhibitors have been developed. Members of the TGF-beta superfamily bind to type I and type II serine/threonine kinase receptors and transduce intra-cellular signaling through Smad proteins. TGF-beta /activin/ myostatin activate Smad2/3, whereas the BMP subfamily activates Smad1/5/8. These pathway-restricted Smads asso-ciate with Co-Smad, Smad4 and translocate into the nucleus, and regulate transcription of target genes. Smad6/7 are in-hibitory Smads that serve as negative regulators of signaling of the TGF-beta family.

Since TGF-beta signaling is involved in pathogenesis and progression of various diseases, TGF-beta inhibitors are prom-ising as novel drugs for the treatment of cancer, muscular dystrophy, osteoporosis and fibrosis. Myostatin inhibitors such as monoclonal myostatin antibodies, follistatin and my-ostatin propeptide could be promising lead compounds in drug development for muscular dystrophy.

TGF-beta Inhibitors and Cancer

TGF-beta has a dual role in tumor progression, both as a tumor suppressor and tumor promoter. Targeting a TGF-beta tumor promoting activity is attractive since tumors are often resistant to the growth-inhibitory ef-fect of TGF-beta at the time of tumor detection. In particular, TGF-beta plays an important role in promoting metastasis. In fact, one report showed that lifetime exposure to a soluble TGF-beta antagonist protects against metastasis without ad-verse side effects. Thus, it is predicted that inhibitors of the TGF-beta signaling pathway would result in delays in tumor progression and improved survival. Several clinical trials inhibiting TGF-beta signaling by various strategies indi-cate that TGF-beta inhibition may be a promising option for cancer therapy.

Initially, the dominant negative form of TGF-beta RII was used to block TGF-beta activity, and has been shown to prevent epithelial–mesenchymal transition]. Dominant negative TGF-beta RII also suppresses tumorigenic-ityand metastasis of thymoma and mammary tumors. Antisense oligonucleotides against TGF-beta are good clinical candidates for treatment of cancer and fibrosis. Monoclonal antibodies against TGF-beta 1 and beta 2, called lerdelimumab and metelimumab, respectively, have been developed and are now in phase II/III studies in nephropathy, fibrosis, glioblastoma, non-small cell lung carcinoma, and colorectal cancer. Above all, small chemical TGF-beta in-hibitors also have promising therapeutic potential.

TGF-beta Inhibitor Perspectives

Inhibitors for the TGF-beta superfamily have great potential for multiple clinical applications. Inhibition of either TGF-beta or activin could delay cancer progression and prevent fibro-sis. Myostatin inhibition is a promising novel thera-peutic strategy to treat muscular disorders, including muscu-lar dystrophy. Targeting either BMP ligand or BMP inhibitors could be beneficial for osteoporosis and re-generation of bone and teeth.

Several molecules can inhibit TGF-beta family members. Chemical inhibitors for the TGF-beta family could be adminis-tered either intravenously or orally. Natural proteins and antibodies were intraperitoneally administered. In the case of therapy of glioma, intracerebral and intrathecal infusion of antisense oligonucleotide has been trialed. Development of TGF-beta inhibitors and innovation of new technology for in vivo drug delivery will undoubtedly increase options for therapyagainst cancer and musculoskeletal disorders in which the TGF-beta family plays a significant role.


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