Technology Overview

The Smad transduction pathway of the transforming growth factor-beta (TGF-β) superfamily is an excellent focal point for the development of innovative new drugs to treat unmet medical needs. The TGF-β superfamily encompasses a large group of extracellular proteins, including TGF-β, activin and the bone morphogenic proteins (BMPs). Cellular signaling by the BMPs and all members of the TGF-β superfamily is known to be mediated by the Smad proteins. The TGF-β branch of the superfamily activates Smad-2 and Smad-3, and the BMP branch activates Smad-1, Smad-5, and Smad-8. The Smad pathway plays important role in the pathogenesis of a variety of diseases, including kidney disease.

BMPs have many known biological functions, including bone growth and the regulation of growth, differentiation, chemotaxis, and apoptosis of various cell types such as epithelial, mesenchymal, haematopoietic and neuronal cells. The mechanism of action of the BMPs has been well documented in the scientific literature and they are used clinically for bone repair. BMPs, however, are limited to this use because of cost of production and side effects associated with ectopic bone formation.

Activation of the Smad proteins occurs through a heteromeric complex consisting of Type I and Type II serine/threonine kinase receptors. Type II receptors are constitutively active kinases capable of binding ligands alone, whereas Type I receptors bind ligands only in cooperation with specific Type II receptors. There are multiple Type I receptors, known as activin like kinase (ALK) receptors with distinct functional activities (See Figures 1 and 2). Activation of ALK-6 is known to promote bone growth. TGF-β, itself, acts through activation of ALK-5 which can promote both tissue repair but also fibrosis. ALK-2 and ALK-3 activation are known to promote tissue repair and protection against inflammation.

Thrasos designs compounds to target the BMP Type II receptor and known Type I-ALK receptors from the BMP branch of the TGF-β superfamily. Activation of one or more of the BMP ALK receptors leads to phosphorylation of Smads 1,5, and 8 which can then translocate to the cell nucleus (through combination with Smad-4) to activate specific genes. The Company's drug candidates have been shown to bind to both the Type II BMP receptor and selectively bind to the Alk-3 and ALK-2 Type I BMP receptors. The Company's compounds do not bind the ALK 6 receptor and therefore have been shown to be devoid of osteogenic activity (Figures 1 & 2).


	Overview	The Smad transduction pathway of the transforming growth factor-beta (TGF-β) superfamily is an excellent focal point for the development of innovative new drugs to treat unmet medical needs. The TGF-β superfamily encompasses a large group of extracellular proteins, including TGF-β, activin and the bone morphogenic proteins (BMPs). Cellular signaling by the BMPs and all members of the TGF-β superfamily is known to be mediated by the Smad proteins. The TGF-β branch of the superfamily activates Smad-2 and Smad-3, and the BMP branch activates Smad-1, Smad-5, and Smad-8. The Smad pathway plays important role in the pathogenesis of a variety of diseases, including kidney disease. BMPs have many known biological functions, including bone growth and the regulation of growth, differentiation, chemotaxis, and apoptosis of various cell types such as epithelial, mesenchymal, haematopoietic and neuronal cells. The mechanism of action of the BMPs has been well documented in the scientific literature and they are used clinically for bone repair. BMPs, however, are limited to this use because of cost of production and side effects associated with ectopic bone formation. Activation of the Smad proteins occurs through a heteromeric complex consisting of Type I and Type II serine/threonine kinase receptors. Type II receptors are constitutively active kinases capable of binding ligands alone, whereas Type I receptors bind ligands only in cooperation with specific Type II receptors. There are multiple Type I receptors, known as activin like kinase (ALK) receptors with distinct functional activities (See Figures 1 and 2). Activation of ALK-6 is known to promote bone growth. TGF-β, itself, acts through activation of ALK-5 which can promote both tissue repair but also fibrosis. ALK-2 and ALK-3 activation are known to promote tissue repair and protection against inflammation. Thrasos designs compounds to target the BMP Type II receptor and known Type I-ALK receptors from the BMP branch of the TGF-β superfamily. Activation of one or more of the BMP ALK receptors leads to phosphorylation of Smads 1,5, and 8 which can then translocate to the cell nucleus (through combination with Smad-4) to activate specific genes. The Company's drug candidates have been shown to bind to both the Type II BMP receptor and selectively bind to the Alk-3 and ALK-2 Type I BMP receptors. The Company's compounds do not bind the ALK 6 receptor and therefore have been shown to be devoid of osteogenic activity (Figures 1 & 2).