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| Primary information |
|---|
| ID | 16209 |
| Therapeutic ID | Th1722 |
| Protein Name | ADH-1 |
| Sequence | >Th1722_ADH-1
GLKAADNDPTAPPYDSLLVFDYEGSGSTAGSLSSLNSSSSGGDQDYDYLNDWGPRFKKLADMYGGGDD
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| Molecular Weight | NA |
| Chemical Formula | NA |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | NA |
| Description | Adherex's biotechnology compound, ADH-1, targets N-cadherin, a protein present on certain tumor cells and established tumor blood vessels. ADH-1 is currently in clinical development in a combination program with a range of chemotherapeutic agents to investigate the synergistic effects noted in our preclinical models. At the end of 2006, the Company also completed patient enrollment in our single-agent Phase Ib/II and Phase II trials of ADH-1. Cadherins are cell adhesion and cell signaling molecules crucial to the development of tissues, organs and organisms. Agents that target and inhibit cadherin function have the potential to attack the progression of cancer at two distinct points: * Direct targeting of cadherins expressed on cancer cells may disturb cadherin-mediated signaling, leading to apoptosis (death) of cancer cells. * Cadherin inhibitors may exploit the inherent structural weaknesses of the tumor vasculature, causing angiolysis (disruption of blood vessels) and tumor damage. As many tumors become more aggressive, invasive, and malignant, researchers have found that N-cadherin is expressed in greater amounts, making it an important target for developing anti-cancer treatments. Poorly differentiated, highly invasive carcinomas are characterized by over-expression of N-cadherin (as opposed to E-cadherin). This change in primary cadherin expression causes the epithelial cells to lose their tightly adherent, polarized and well-defined shape and become loosely adherent, flattened and migratory. Such cadherin switching promotes properties such as dedifferentiation, local invasion and metastasis, leading to poor prognosis. ADH-1 may have utility in a wide variety of cancers as N-cadherin is overexpressed in a variety of tumors. As tumors progress to become higher grade, invasive and more metastatic, the frequency of N-cadherin expression generally rises. |
| Indication/Disease | Investigated for use/treatment in breast cancer, cancer/tumors (unspecified), melanoma, ovarian cancer, and solid tumors. |
| Pharmacodynamics | ADH-1 is a biotech compounds that targets N-cadherin, a protein present on certain tumor cells and established tumor blood vessels. Cadherins are cell adhesion and cell signaling molecules crucial to the development of tissues, organs and organisms. Agents that target and inhibit cadherin function have the potential to attack the progression of cancer at two distinct points: * Direct targeting of cadherins expressed on cancer cells may disturb cadherin-mediated signaling, leading to apoptosis (death) of cancer cells. * Cadherin inhibitors may exploit the inherent structural weaknesses of the tumor vasculature, causing angiolysis (disruption of blood vessels) and tumor damage. The compound is indicated for treatment of a variety of invasive carcinomas and ADH-1 has been shown to be synergistic with taxane-based chemotherapy in the systemic treatment of ovarian cancer xenografts. |
| Mechanism of Action | While ADH-1 has a single molecular target, N-cadherin, we believe its anti-cancer effect results from two distinct mechanisms of action - apoptosis and tumor vessel angiolysis. N-cadherin appears to act as a tumor cell survival factor. In cell culture studies, inhibition of N-cadherin binding between tumor cells has been shown to cause apoptosis of tumor cells, we believe as a result of disrupting the cadherin-regulated cell survival signals. ADH-1 also appears to disrupt the blood vessels needed for cancerous tumors to grow and flourish, with hemorrhaging having been noted in both our clinical and preclinical studies. We believe the mechanism for this disruption is either a competitive inhibition of the binding of cadherins between the endothelial cells of the tumor blood wall or apoptosis in tumor cells that form a part of the blood vessel wall, each leading to leakage and rupture of these vessels. The latter involves the phenomenon of tumor "mosaicism," in which tumor cells form a portion of the vascular wall (along with the endothelial cells). Induction of cell death of these tumor cells would result in tumor vascular disruption. |
| Toxicity | NA |
| Metabolism | NA |
| Absorption | NA |
| NA |
| Clearance | NA |
| Categories | NA |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | NA |
| Brand Name | NA |
| Company | NA |
| Brand Description | NA |
| Prescribed For | NA |
| Chemical Name | NA |
| Formulation | NA |
| Physical Appearance | NA |
| Route of Administration | NA |
| Recommended Dosage | NA |
| Contraindication | (4R,7S,10S,13S,16R)-16-acetamido-13-(1H-imidazol-5-ylmethyl)-10-methyl-6,9,12,15-tetraoxo-7-propan-2-yl-1,2-dithia-5,8,11,14-tetrazacycloheptadecane-4-carboxamide |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |