Alchemix® Fact Sheet

What is Alchemix?

Access’ proprietary Alchemix project is based upon small molecule cytotoxic compounds that can attack tumor cells by several different modes of action. Alchemix compounds combine the anticancer mechanisms of known and mechanistically distinct cytotoxics: cisplatin and doxorubicin. By examining structure-activity relationships of related molecules, Access’ collaborators at the University of Bradford in the U.K. have identified a number of promising candidate compounds and one of these compounds will likely be advanced shortly as a preclinical development candidate. By attacking tumor cells in several ways, the Alchemix compounds have the potential to overcome one of the major problems in treating cancer patients - drug resistance.

Drug Resistance in Chemotherapy

Tumors which are initially sensitive to certain cytotoxic compounds almost invariable become less sensitive to that drug on continued treatment. This occurs because cells which survive the initial drug treatment adapt to resist future treatment. Patients that become resistant to one drug (or a combination of drugs) have to be treated with other drugs, to which patients are again likely to develop resistance.

The following schematic depicts a single tumor cell, and provides an overview of resistance mechanisms that affect two important cytotoxic anticancer agents: doxorubicin and cisplatin, which are representative of anticancer compounds that work primarily through (respectively) intercalation and the formation of chemical bonds to DNA:

Most cytotoxic compounds are effective through a single primary mechanism. By providing several powerful modes of attacking tumor DNA, the Alchemix series of molecules have the potential to delay the onset of resistance, and remain effective for a longer period.

The Multiple Modes of Action of Alchemix

The Alchemix compounds bring together structural features from intercalating, alkylating, and topoisomerase II inhibitory anticancer compounds to provide multiple features in one molecule. Thus, the Alchemix compounds should be able to attack DNA by one of several mechanisms. There is also the possibility that the Alchemix compounds can attack DNA by two or more mechanisms at the same time; for example, one Alchemix molecule both intercalates and alkylates DNA. There is a huge potential benefit by using this type of approach.

Drugs which are intercalators are able to insert themselves into the double helix of DNA, where they disrupt the function and reproduction of DNA. But intercalators are only loosely bound to DNA, and are easily removed - or they simply move away. This can be likened to pushing a key into a lock. Without turning, the key is easily removed from the lock.

But if the interchelator can, through a separate function called alkylation, form a stable chemical bond to the DNA once it is inserted in the double helix, it becomes much more difficult to remove. From the key analogy: the key is turned, and can only be removed by employing two actions instead of one. In the same way, DNA repair following the intercalation and alkylation by an Alchemix molecule would involve two distinct repair steps; breaking the chemical bond then removal of the intercalated molecule. Furthermore, one of the enzymes responsible for repair of DNA is topoisomerase II, and it has been shown that Alchemix molecules also inhibit the function of this enzyme. Thus, Alchemix not only damages tumor DNA, but inhibits one of the key processes that repairs the damage.

Consequently, resistance mechanisms of cancer cells that inhibit cytotoxic compounds with one primary mode of action may be less effective on an Alchemix molecule because of the availability of multiple modes of action.

Alchemix Efficacy Data

In vitro studies have demonstrated that Alchemix can overcome both anthracycline and platinum resistance in tumor cells, as shown in the following table

In addition, the superiority of Alchemix over cisplatin and epirubicin in suppressing tumor growth was demonstrated in a human xenograft tumor model (Pors et al, Molecular Cancer Therapeutics, 2003, 2, 607-610).

Future Development

The Alchemix program is currently in preclinical development. Several promising lead compounds have been made and tested, and Access anticipates that the most promising compound from the series will be selected shortly as the primary development candidate.