ADH-1

Identification

Logo pink
Are you a
new drug developer?
Contact us to learn more about our customized products and solutions.
Name
ADH-1
Accession Number
DB05485
Type
Biotech
Groups
Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
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.

Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
>>uniprot|Q80XX1|Q80XX1_9MURI N-cadherin (Fragment).
GLKAADNDPTAPPYDSLLVFDYEGSGSTAGSLSSLNSSSSGGDQDYDYLNDWGPRFKKLA
DMYGGGDD
Download FASTA Format
Synonyms
Not Available
International/Other Brands
Exherin
Categories
Not Available
UNII
B058ME29VU
CAS number
Not Available

Pharmacology

Indication

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.

Absorption
Not Available
Volume of distribution
Not Available
Protein binding

ADH-1 binds to and inhibits N-cadherin.

Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Mariotti A, Perotti A, Sessa C, Ruegg C: N-cadherin as a therapeutic target in cancer. Expert Opin Investig Drugs. 2007 Apr;16(4):451-65. [PubMed:17371194]
  2. Li H, Price DK, Figg WD: ADH1, an N-cadherin inhibitor, evaluated in preclinical models of angiogenesis and androgen-independent prostate cancer. Anticancer Drugs. 2007 Jun;18(5):563-8. [PubMed:17414625]
  3. Shintani Y, Fukumoto Y, Chaika N, Grandgenett PM, Hollingsworth MA, Wheelock MJ, Johnson KR: ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression. Int J Cancer. 2008 Jan 1;122(1):71-7. [PubMed:17721921]
External Links
PubChem Substance
347910167
Wikipedia
ADH-1

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAcinar Cell Adenocarcinoma of the Pancreas / Adenocarcinoma of the Gallbladder / Adenocarcinoma of the Pancreas / Adult Primary Cholangiocellular Carcinoma / Advanced Adult Primary Liver Cancer / Ampulla of Vater Adenocarcinoma / Cholangiocarcinoma of the Gallbladder / Duct Cell Adenocarcinoma of the Pancreas / Gallbladder Adenocarcinoma / Localized Unresectable Adult Primary Liver Cancer / Pancreatic Adenocarcinoma Metastatic / Periampullary Adenocarcinoma / Recurrent Adult Primary Liver Cancer / Recurrent Gallbladder Cancer / Recurrent Pancreatic Cancer / Stage II Gallbladder Cancer / Stage III Ampulla of Vater Cancer / Stage III Intrahepatic Cholangiocarcinoma / Stage III Pancreatic Cancer / Stage IIIA Gallbladder Cancer / Stage IIIA Hilar Cholangiocarcinoma / Stage IIIB Gallbladder Cancer / Stage IIIB Hilar Cholangiocarcinoma / Stage IV Ampulla of Vater Cancer / Stage IV Pancreatic Cancer / Stage IVA Gallbladder Cancer / Stage IVA Hilar Cholangiocarcinoma / Stage IVA Intrahepatic Cholangiocarcinoma / Stage IVA Pancreatic Cancer / Stage IVB Gallbladder Cancer / Stage IVB Hilar Cholangiocarcinoma / Stage IVB Intrahepatic Cholangiocarcinoma / Stage IVB Pancreatic Cancer1
1, 2CompletedTreatmentNeoplasms2
1, 2TerminatedTreatmentNeoplasms1
2CompletedTreatmentNeoplasms1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Drug created on November 18, 2007 11:25 / Updated on June 04, 2019 06:17