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Drugging the 'undruggable'

By Mike Nagle , 30-May-2007

Over 50 per cent of proteins in the body are considered too difficult to target with drugs; they are 'undruggable'. Yet it is exactly these molecules US pharma firm Avalon is focussing on.

Using its in-house drug discovery tool, Avalon is attempting to build a pipeline of first-in-class anticancer drugs and its lead compound is currently in Phase I clinical trials. To help speed the process along, the company has recently raised $20m (€14.9m) in a private sale of common stock.


In order to find drugs that can modulate 'undruggable' targets, Avalon has shunned the conventional drug discovery processes that sometimes fail to account for side-effects caused by drugs interacting with multiple targets, in favour of a systems biology approach.


"It is estimated that at high as 80 per cent of the key oncogenic targets are not druggable because only enzymatic targets are amenable to conventional screening technologies. Other kinds of proteins in the cell, like transcription factors and transport proteins, can not be used for conventional high-throughput compound library screening," Dr Ken Carter, Avalon CEO, explained to DrugResearcher.com.


However, using their AvalonRx tool, Carter said his scientists are in a position to screen for new drugs against virtually any target or pathway.


The company now has nine cancer programmes in its pipeline, several partnered with larger pharma companies such as Merck & Co. and Novartis and an inflammation programme with MedImmune (likely to soon be part of AstraZeneca). Although their most advanced, and only clinical, programme remains without a partner, Carter hopes to team up the development with another company in the future. AVN944 was originally developed by Vertex before being licensed to Avalon over two years ago in a $73m deal.


The drug is currently, or will be in future trials, tested against leukaemia, lymphoma, myeloma and pancreatic cancer. Carter envisions it could be used as a monotherapy in some haeme malignancies. However, current results suggests the drug has a good safety profile and so Avalon is likely to test it in a broad range of combination therapies on the basis that it will cause additional fragility in tumour cells allowing other drugs to be used at lower doses or to be more effective at current doses.


Since then, Avalon has used its technology to discover more about the drugs mechanism and specificity. AVN944 is a very specific small molecule inhibitor of inosine monophosphate dehydrogenase (IMPDH), an essential enzyme in the metabolism of purines, acting as a catalyst in the production of guanine nucleotides, which are required for many critical processes, such as DNA synthesis. The drug also reduces GTP pools within cells which are key to cellular signalling.


When GTP pools are depleted, normal cells are quite stable and essentially hibernate. Conversely, cancer cells begin to commit suicide because of their programmed drive to replicate DNA.


"Thus, inhibiting IMPDH is a safer form of inhibiting DNA replication in cancer cells as compared to more cytotoxic drugs that directly interacts with and damage DNA in all cells," said Carter.


Previous attempts to design drugs to inhibit IMPDH have met with failure as cancer therapies. For example, Roche's CellCept (mycophenolate) was deemed to have too many side-effects for it to be used as a cancer therapy However, since IMPDH is also crucial to the production of white blood cells in the immune system, CellCept is used, in lower doses, as an immunosuppressant in organ transplant patients.


AvalonRx works by first knocking out a gene's activity using RNA interference (RNAi) technology. The activity of other gene's are effected by this is then measured - whether these genes become more or less active. This generates a kind of gene signature that is dependant on the RNAi knockout. The researchers then screen for small molecules with signatures that mimic those seen with RNAi.


The technology has other advantages over conventional techniques. Carter described it as 'agnostic' with regard to exactly which target in the pathway gets hit. Therefore, it is the equivalent of screening for multiple nodes in a pathway at once he explained. Also, drug optimization occurs in the context of living cells, not against single targets in isolated test tubes, allowing more informed decisions at each step of the development process.


Although, Avalon has spent around $50m over the last five years developing the system, once its advantages are taken into account, AvalonRx could significantly reduce development times, and therefore save money.


"The technology allows you to go directly from an RNAi bench work experiment to a small molecule candidate for optimisation into a drug within months," said Carter.


However, one disadvantage is that this method means the exact target of the drug has to be 'reverse discovered', although Carter went on to point out that he believes: "the myopic focus on individual targets has led to inappropriate reductionists thinking about the mechanism of drugs which has slowed the development of novel, more synoptic approaches to drug discovery."