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Inhibitors of the TGF-Β Superfamily and Their Clinical Applications

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Inhibitors of the TGF-Β Superfamily and Their Clinical Applications Mini-Reviews in Medicinal Chemistry, 2006, 6, 1255-1261 1255 Inhibitors of the TGF- Superfamily and their Clinical Applications K. Tsuchida1,*, Y. Sunada2, S. Noji3, T. Murakami1, A. Uezumi1 and M. Nakatani1 1Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan; 2Division of Neurology, Department of Internal Medicine, Kawa- saki Medical School, 577 Matsushima, Kurashiki-City, Okayama 701-0192, Japan; 3Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, 2-1 Minami-Jyosanjima-cho, Tokushima 770- 8506, Japan Abstract: The transforming growth factor- (TGF-) superfamily includes TGF-s, activin, myostatin and bone morpho- genetic proteins. Misregulation of the activity of TGF- family members is involved in pathogenesis of cancer, muscular dystrophy, obesity and bone and tooth remodeling. Natural inhibitors for the TGF- superfamily regulate fine-tuning of activity of TGF- family in vivo. In addition to natural inhibitors for the TGF- family, soluble forms of receptors for the TGF- family, blocking monoclonal antibodies and small chemical TGF- inhibitors have been developed. In this review, we summarize recent advances in our understanding of inhibitors for the TGF- superfamily and their medical applica- tions. Key Words: TGF-, activin, BMP, cancer, fibrosis, follistatin, myostatin, muscular dystrophy. INTRODUCTION of receptors for the TGF- superfamily, blocking mono- The transforming growth factor- (TGF-) superfamily clonal antibodies, and small molecule receptor kinase inhibi- includes TGF-s, activin, myostatin and bone morphogenetic tors have recently been developed. proteins (BMPs) [1]. They are involved in many biological Since TGF- signaling is involved in pathogenesis and responses including growth and differentiation of various progression of various diseases, TGF- inhibitors are prom- cell types. Misregulation of specific TGF- family members ising as novel drugs for the treatment of cancer, muscular is involved in pathogenesis of certain types of cancer, fibro- dystrophy, osteoporosis and fibrosis. Myostatin inhibitors sis, diseases affecting skeletal muscle, and osteoporosis [2]. such as monoclonal myostatin antibodies, follistatin and my- Thus, proteins and chemicals that regulate TGF- family ostatin propeptide could be promising lead compounds in members could be used as drugs for treatment of human dis- drug development for muscular dystrophy. BMP signaling is eases. involved in osteogenesis and tooth development. Therefore, Members of the TGF- superfamily bind to type I and BMP inhibitors could be applicable for osteoporosis and type II serine/threonine kinase receptors and transduce intra- tooth regeneration. cellular signaling through Smad proteins. TGF-/activin/ In this mini-review, we summarize recent advances in myostatin activate Smad2/3, whereas the BMP subfamily our understanding of TGF- inhibitors and their potential activates Smad1/5/8. These pathway-restricted Smads asso- medical applications. ciate with Co-Smad, Smad4 and translocate into the nucleus, OUTLINE OF THE TGF- SUPERFAMILY and regulate transcription of target genes. Smad6/7 are in- hibitory Smads that serve as negative regulators of signaling TGF- family members are pleiotropic cell signaling of the TGF- family [1]. Signaling of the TGF- family is proteins that play essential roles in tissue homeostasis and regulated by extracellular ligand-binding proteins. Follistatin development [1]. One of the most salient characteristics of and related molecules regulate activin/myostatin [2]. Noggin, TGF- family members is inhibition of growth of various chordin, Cerberus and differential screening-selected gene cell types. TGF- is involved in inhibition of cancer cell aberrative in neuroblastoma (DAN) families are regulators of growth. TGF- induces cell cycle arrest through upregula- BMP family members. tion of cyclin-dependent kinase (CDK) inhibitors p21, p27 Furthermore, TGF- receptors are dynamically regulated and p15, resulting in the inhibition of entry through the G1- by trafficking of receptors by clathrin-mediated endocytosis phase into the S-phase [1,3]. This property of TGF- has and the lipid raft-caveolar pathway [1]. gained much attention for its role in tumor suppression in tumorigenesis. In the later phase of cancer progression, tu- As mentioned above, natural binding proteins for the mor cells become resistant to growth inhibition by TGF-, TGF- superfamily exist and play an important role in nega- and cancer cells secrete TGF-. TGF- secreted by cancer tive regulation of TGF- signaling. In addition, soluble forms stimulates the neighboring epithelial cells and promotes can- cer progression through epithelial–mesenchymal transdiffer- entiation, and promotes metastasis of malignant cells through *Address correspondence to this author at the Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), mediating changes in cytoskeletal architecture [1,4]. There- Fujita Health University, Toyoake, Aichi 470-1192, Japan; Tel: +81-562- fore, TGF- signaling offers an attractive target for cancer 93-9384; Fax: +81-562-93-5791; E-mail: [email protected] therapy. TGF-s signal through their own type II receptor 1389-5575/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd. 1256 Mini-Reviews in Medicinal Chemistry, 2006, Vol. 6, No. 11 Tsuchida et al. (TRII) and type I receptor (activin receptor-like kinase 5 receptors [19]. However, the majority of TGF- family bind- (ALK5)), that are distinct from the type II and type I recep- ing proteins in the extracellular space sequester ligands to tors which activins or BMPs utilize. Several strategies such block ligand-binding to receptor serine kinase on the target as the use of antisense oligonucleotides for TGF-, mono- cells. Research on the mechanism of extracellular regulation clonal TGF- antibodies, dominant negative TRII, and of TGF- signaling by binding proteins provides clues for small drug molecules that inhibit TGF- receptor I kinase the treatment of diseases caused by misregulation of the have shown great promise in preclinical studies [4]. TGF- signaling pathway [20,21]. Activins are homo- or hetero-dimers composed of two Follistatins are best characterized as activin-binding pro- subunits and belong to the TGF- superfamily. Follistatins teins [5,20,22]. Follistatin is a single-chain protein with a are high affinity activin-binding proteins and efficiently neu- molecular mass of 31–39 kDa. Alternative splicing of a sin- tralize activin functions [2,5]. Activin, inhibin and follistatin gle gene and partial proteolysis produces multiple forms of are well-recognized as endocrine hormones regulating go- follistatins. All forms of follistatins have an N-terminal do- nadal functions [2]. However, recent investigation reveals main and three cysteine-rich domains, called follistatin do- that alteration of activin signaling, like TGF-, is directly mains, and demonstrate high affinity binding to activins with involved in tumor progression. Activins signal through het- estimated Kd values of 500–800 pM. Recently, the structures eromeric complexes of activin type II receptors (ActRIIA of the follistatin–activin complex were reported [23] (Fig. and ActRIIB) and type I receptor (ALK4). Two 8-bp poly- (1)). Two follistatin molecules encircle activin A, neutraliz- adenine [(A)8] tracts of the ActRIIA gene were identified as ing the ligand by burying one-third of its residues and recep- targets for frameshift mutations in gastrointestinal cancers tor binding sites. Both type I and II receptor binding sites of [6]. ALK4 (ACVR1B) gene mutations have also been found activin are blocked by follistatin binding to activin (Fig. (1)). in pancreatic carcinoma [7]. Human genes for Smad2 and Gene knockout studies have revealed that follistatin-deficient Smad4 (Dpc4), which act as downstream effectors of ac- mice show numerous phenotypes including musculoskeletal tivins, TGF- and myostatin, map to chromosome 18q and and cutaneous abnormalities [24]. In particular, follistatin- are mutated in colorectal and pancreatic carcinomas [8,9]. deficient mice show a reduction in the muscle mass of the These findings indicate that alteration of the activin signaling diaphragm and intercostal muscles. In addition, rib defects pathway is involved in tumorigenesis. and a decreased number of lumbar vertebrae are observed in follistatin gene knockout mice. This finding suggests that Cripto, which is the founding member of the epidermal follistatin serves as an inhibitor not only for activins but also growth factor-Cripto, FRL-1, and Cryptic (EGF-CFC) fam- for other growth and differentiation factor (GDF)/BMP sub- ily, has a role as a co-receptor for nodal [10]. In addition, families like myostatin and GDF11 [13,24,25]. In fact, recent Cripto binds directly to activin B and inhibits activin B sig- characterization reveals that follistatin is an efficient inhibi- naling in breast cancer [10]. Blocking Cripto function by a tor of myostatin and the closely related TGF- family mem- monoclonal antibody suppresses tumor cell growth in vivo, ber, GDF11 [26]. Follistatin-related gene, called FLRG, was most probably through augmentation of activin B signaling recently identified that has similar ligand binding specificity by sequestering Cripto from activin B [10]. Taken together, and structure as follistatin [27–29]. However, several differ-
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