ADH-1

Identification

Generic Name

ADH-1

DrugBank Accession Number

DB05485

Background

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.

Type

Biotech

Groups

Investigational

Biologic Classification

Protein Based Therapies
Other protein based therapies

Protein Chemical Formula

Not Available

Protein Average Weight

Not Available

Sequences

>>uniprot|Q80XX1|Q80XX1_9MURI N-cadherin (Fragment).
GLKAADNDPTAPPYDSLLVFDYEGSGSTAGSLSSLNSSSSGGDQDYDYLNDWGPRFKKLA
DMYGGGDD

Download FASTA Format

Synonyms

• Cys-His-Ala-Val-Cys
• l-cysteinamide, n-acetyl-l-cysteinyl-l-histidyl-l-alanyl-l-valyl-, cyclic (1-5)-disulfide

External IDs

• NSC-729477

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Pharmacology

Indication

Investigated for use/treatment in breast cancer, cancer/tumors (unspecified), melanoma, ovarian cancer, and solid tumors.

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Contraindications & Blackbox Warnings

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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

Adverse Effects

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Toxicity

Not Available

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Not Available

Food Interactions

Not Available

Products

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International/Other Brands

Exherin

Categories

Drug Categories

Not Available

Chemical TaxonomyProvided by Classyfire

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

Affected organisms

Not Available

Chemical Identifiers

UNII

B058ME29VU

CAS number

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. [Article]
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. [Article]
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. [Article]

External Links

PubChem Substance

347910167

Wikipedia

ADH-1

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2	Completed	Treatment	Neoplasm	1
1	Completed	Treatment	Adenocarcinoma of the Gallbladder / Carcinoma of Ampulla of Vater / Pancreatic Adenocarcinoma / Pancreatic Adenocarcinoma Metastatic / Pancreatic Carcinoma Stage III / Stage III Ampulla of Vater Cancer / Stage III Intrahepatic Cholangiocarcinoma / Stage IIIA Gallbladder Cancer / Stage IIIA Hilar Cholangiocarcinoma / Stage IIIB Gallbladder Cancer / Stage IIIB Hilar Cholangiocarcinoma / Stage IV Ampulla of Vater 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 Cancer	1
1, 2	Completed	Treatment	Neoplasm	2
1, 2	Terminated	Treatment	Neoplasm	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Not Available

Prices

Not Available

Patents

Not Available

Properties

State

Liquid

Experimental Properties

Not Available

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Drug created at November 18, 2007 18:25 / Updated at December 03, 2022 09:37