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ArQule Scientists on Incorporating HCS into Cancer Drug Discovery

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Part one of a two-part series. Click here to read part two.

At A Glance

Mark Ashwell, vice-president, Drug Discovery Chemistry

Dave Leggett, senior project manager (oncology programs)

Bin Zhang, senior investigator, Chemical Biology (manages high-content screening)

Andrew Smellie, senior investigator II, Discovery Informatics and Modeling


ArQule began its transition from a chemistry services company to a biotech firm with designs on its own drug discovery approximately at the same time that high-content image-based screening began to find its way into the drug-discovery process. It's no coincidence, then, that the Woburn, Mass.-based company, like many of its competitors, adopted high-content screening into its own discovery process, which revolves primarily around anti-cancer compounds.

Several ArQule researchers recently published a research paper in the Oct. 18 online edition of the Journal of Biomolecular Screening that served as a proof of principle for using HCS to identify small molecules that induce mitotic arrest. The scientists involved in that particular research also reflect ArQule's general approach to the use of HCS: the company prefers to assign different people to each part of the HCS process, from assay design to instrumentation to image analysis and informatics.

ArQule also is a real-world example of a company that is rolling with the changes in a nascent and frequently volatile market, as it has already exchanged its original high-content screening platform, a Beckman Coulter IC 100, for an IN Cell Analyzer from GE Healthcare.

Last week, the ArQule scientists involved in the adoption of HCS technology and the JBS paper discussed their experiences with CBA News.

When and how was ArQule founded?

MA: ArQule's history goes back about 12 years, and it began in the area of parallel chemistry — synthesis of large libraries or collections of small molecules for commercial sale. To put that into perspective, that time in the industry that we're talking about, providing that service for many pharmaceutical companies, ArQule began to establish a reputation for service provision and aiding the discovery of pharmaceutical discovery candidates for third parties. Around five or six years ago, the marketplace for such services was very different from when the company was founded, and several initiatives were put in place to transform the company. While developing our proprietary chemistry technology, which is applicable to finding leads, developing those leads into potential clinical candidates, and moving those out into pharmaceutical development, we needed and looked to bring a lot of those downstream activities internally, and looked to build an organization on the strength of the chemistry. As we looked around and tried to envisage how that would transform such a chemical services organization, we needed a critical component that linked the chemistry with the biology. So just over two years ago, ArQule acquired a company called Cyclos, a small company that developed an increased understanding about the biology of cancer cells, and using that knowledge to develop small molecules able to affect pathways and processes in cancer cells, preferentially over normal cells. Over the last couple of years — and one of the activities we're talking about here is high-content screening — we've looked to marry our ability to do efficient high-throughput chemistry with ways to screen and differentiate molecules for our own internal purposes, so that we can become a biotech company and develop those small molecules.

So you're focused 100 percent on internal drug discovery?

MA: Yes. Last week we announced to the public that we would be closing our chemical service business at the end of May 2006, focusing completely on our ability as a biotech organization to identify and develop our new generation of rationally designed small molecules.

And this is primarily chemotherapeutic drug discovery?

MA: It is primarily, and our focus is on molecules that we expect to have an increased therapeutic window because we are not relying on simple chemotoxicity. We are looking to affect, fundamentally, pathways that affect cancer cell death, preferentially over normal cell death.

How did you come to begin using high-content screening in your drug discovery program?

MAl: We've actually got many different activities going. HCS is one of the areas, because it gives us insight into a system that is closer to an in vivo setting. It's a whole cell-based activity for our molecules. We looked at ways to get a leg up on identifying small molecules that have biological activity of interest, but also that affect cell pathways. If you're a drug discoverer or developer, the quicker you can get molecules that affect internal cell pathways, you can effectively move ahead of simple target screening. So it was very attractive to us because from a discovery point of view, it gives you the ability to separate your molecules from those that have a cellular effect versus those that just affect an isolated target. It potentially accelerates our drug discovery, because we don't have to engineer into those small molecules the ability to cross cell membranes. If we have a cellular effect, we can safely assume the molecules penetrate cells, cancer cells especially, which is fundamental to being efficient. And it's complementary to our more traditional target-based screening, where we take an isolated target and screen our compound collections against those, which a lot of people are more familiar with.

Can you describe your Activated Checkpoint Therapy platform — what that means, and how high-content screening fits into that?

DL: The Activated Checkpoint Therapy is a model that our CSO, Chiang Li, has been working on for many years. Basically, in a cell's normal progression through the cell cycle, there are various checkpoints in the cycle where the cell will pause and check itself to verify that it's ready to progress to the next stage of the cycle. If it isn't ready to move on, through damage, et cetera, the cell has an internal program to kill itself or fix itself depending on how severe the damage is. And that's a normal progression for a cell. In cancer cells, the cells must evolve and mutate in order to overcome these checkpoints, to progress and become cancerous and divide in an uncontrolled fashion. We look to identify compounds or pathways that can reactivate these checkpoints. The model is that if you have a drug that reactivates checkpoints, and give it to normal cells and cancer cells, the normal cells will activate the checkpoint, pause at the checkpoint, but since they're normal and don't have damage, they will proceed on to the next phase in the cell cycle. However, in cancer cells, when you reactivate these checkpoints, the cells will check themselves, find out that they indeed have damage, and will initiate the cell death pathway. Therefore, in this paradigm, you will get very selective cell kill. The pilot program that we have for this, which is currently in the clinic, is a proof-of-concept compound around this. The other important point is that this is a general mechanism in all cells, so this is expected to be efficacious against a broad range of cancer cells. That's in fact what we see pre-clinically.

In the Journal of Biomolecular Screening paper, though, your group screened for molecules that induced mitotic arrest, not for molecules that worked via the mechanism you described.

DL: That's correct. The Activated Checkpoint Therapy is our proprietary biological platform; however, we don't completely limit ourselves to that biological technology. There are many attractive biological targets and phenotypic targets that are worthy of pursuit, and we will continue to do that, as well.

In the paper, you described how you screened somewhere around 13,000 small molecules from your collection of about 1 million, using HCS and the Kolmogorov-Smirnov test, to identify inducers of mitotic arrest. What were your major results?

MA: We felt it was important to publish the work because it brings a lot of our paradigms together in an efficient way. We are very much interested in discovering small molecules that have the ability to affect critical activities, and mitotic arrest is certainly one of those in cancer cells. The goal of this work was to take a well-characterized small subset of our large compound collection, and we were actually able to pass through a significant number of those markers quite quickly and efficiently using this technology. The purpose of this paper was to illustrate that approach, and to bring the knowledge to a wider audience. The fact is that ArQule has these molecules in its own internal compound collection. The one we chose to publish on, is, from our internal perspective, is less interesting to our internal drug discovery than it is to what [methods] we identified. We have an upcoming publication where we talk more in general terms about the number of compounds we got from such screening activities. So it's one of a subset of the 13,000 that we screened and we chose to publish this work around, because it illustrated our approach and the mechanism we used to get to that.

In part two of this interview, which will appear in the 12/26 issue of CBA News, Zhang and Smellie weigh in on changing HCS platforms, dealing with huge amounts of data, and developing algorithms that suit ArQule's particular needs.