SuperGen Inc.

Source: Healthcare Digital

Date :11/08/2007 09:23:38

Cancer is basically the uncontrolled growth of cells within the body, and SuperGen is searching for a way to turn those cells off

Written and produced by James Buchanan & Thomas Venturo

Cytotoxic chemotherapy and radiation are indiscriminate killers.

They are effective at killing some cancer cells, but will often leave other cells damaged but able to repair themselves and resume their uncontrolled growth.

These therapies can also damage healthy cells as well as cancer cells, leaving patients fatigued, feeling ill and prone to opportunistic infections.

For these reasons, researchers in the biotechnology field are developing drugs that target the proteins that allow cancer cells to grow and spread. Since these proteins are not as important to the growth and function of normal cells, they are relatively unharmed. In short, researchers are seeking ways to simply turn off cancer cells.

One company at the forefront of the field is SuperGen Inc., based in Dublin, Calif., which is dedicated to the discovery and rapid development of novel targeted therapies for solid tumors and hematological malignancies. The company is in the process of developing a number of targeted therapeutic anticancer products.

“Unlike many companies in the biotechnology space, we have marketed products that are generating revenue for the company,” says James S. Manuso, Ph.D. chairman, president and CEO of SuperGen. “We expect the revenue stream from these drugs to increase, which will support future investments in the research and development of the next generation of targeted small molecule anticancer drugs.”

He goes on to add, “Most companies in the biotechnology field are not profitable. They are forced to continually go back to the financial markets in order to raise more money to continue their research. We are in an uncommon position because we are self financing our research and development.

“There are a few companies that are profitable, but by-and-large, biotechnology companies are not, and one of the reasons for that is because the costs to develop and market drugs are extremely high.”

The reason why SuperGen has managed to move quickly and place two drugs in the marketplace, says Manuso, is due to time, selection and luck.

“We have been around for 16 years. The company was founded in 1991, and we had the opportunity to acquire the drug Dacogen from Pharmachemie BV in 1999 and to develop it through approval in the U.S.,” he says. “We were also able to acquire Nipent 11 years ago, in 1996, from Warner-Lambert, which was already an approved drug.”

“We were an overnight success that only took 16 years to accomplish,” Manuso jokes, and then describes the means by which the drugs his company creates work to fight cancer.

“The drugs that we are developing typically focus on inhibiting cells at the molecular level to disrupt signals that cause them to grow abnormally and spread,” he says.

This work represents a transition in cancer treatment from traditional anticancer therapies, such as cytotoxic chemotherapy and radiation, to targeted drugs that inhibit aberrant growth or metastatic signals which characterize cancer cells and distinguish them from healthy cells.

This does not necessarily indicate the end of the use of radiation and cytotoxic therapies. Rather, SuperGen’s drugs are likely to be active as single agents to shut down the growth and spread of cancer cells or in combination with other agents to prevent repair mechanisms in damaged cancer cells.

“Specifically, we work with small molecules that target cancer cells,” says Manuso. “We have expertise in developing drugs for liquid cancers [hematology] such as leukemia and the like, but recently our efforts have broadened to include solid tumors [oncology].”

Rapid Discovery

CLIMB is the process developed by SuperGen that it believes will help identify and develop a greater number of drugs than the company’s competition. CLIMB stands for Computational Lead Identification Modeling Biology, which —stated in most simplistic terms — combines the use of computer modeling with the disciplines of chemistry and biology, to find drugs that have a higher probability of working on specific cancer targets.

Manuso says that in order to understand the CLIMB process, it is first important to understand the arena in which the company works.

SuperGen’s work is focused in two primary areas within the signal transduction inhibitor field: inhibition of kinases and protein-protein interactions; and DNA methyltransferase inhibitors.

The first of these refers to inhibiting the biochemical process by which one part of a cell communicates with another. In healthy cells these communications can activate and control the normal growth of a cell. In a cancer cell, the signaling process is essentially unregulated and the cell is growing in an uncontrolled manner or engaged in some other uncontrolled behavior.

SuperGen is developing drugs that can specifically target the proteins involved in transmitting these aberrant signals, and thereby regain control over that signaling process to essentially turn the cell off.

“Research in this particular area represents an important step in cancer treatment,” says Manuso.

The second of these two areas – DNA methyltransferase (DNMT) inhibitors – refers to the ability to remove methyl groups from DNA which can restore the function of tumor suppressor genes.

Cancer cells will commonly turn off genes that can suppress tumor growth by modifying the DNA of these tumor suppressor genes through the addition of methyl groups by the enzyme DNMT. The use of inhibitors of DNMT by entities such as Dacogen has proven effective in restoring normal growth in cancer cells.

“We are currently developing second generation inhibitors of DNMT which we believe will be very important in treating cancer in the future as almost all tumor types show some degree of gene silencing through aberrant methylation,” Manuso says.

Making what is already very challenging work more difficult is the fact that no two cancer cells are alike. Already, the number of cancer targets of which researchers have a good understanding of structure and function is placed in the tens of thousands.

Currently the company has ten programs that fit either of the above descriptions in its development pipeline. The most advanced of these, MP470, is a tyrosine kinase inhibitor.

While it is not yet on the market, MP470 was identified and early testing was done through in-silico computer simulation. The in-silico approach is an important component of SuperGen’s CLIMB drug discovery, research and development strategy.

“Many companies in the drug discovery field today use in-silico processes to some degree,” says Manuso. “Most do what is called high throughput screening, where they physically screen a whole library of compounds and try to rapidly run through the process of testing each one against a particular cancer target in a high throughput fashion. We consider that approach as a high throughput/low content strategy.

“We approach discovery with a low throughput/high content strategy,” Manuso says. “We start by creating computer models of a cancer target.

In a perfect world we would know the crystal structure of the cancer target, but we don’t operate in a perfect world. In the absence of a known crystal structure, we can create a model based on the amino acid sequence of the target, based on homology to known protein structures with similar amino acid sequences.”

Once a model has been created, the company utilizes powerful clusters of computers to screen up to several million computer-based structures, evaluating their interactions with the models of the cancer target over several iterations. From these in-silico screens, the structures that are predicted to be the best inhibitors of the target protein and have the best drug-like properties are tested to confirm their activity.

“We develop a list of 100 to 200 structures using our CLIMB technology that look like they would hit the target,” says Manuso. “Since our process is iterative and applies adaptive algorithms, it is critical that we test our predictions and feed the results of our predictions back into CLIMB to continually improve the effectiveness of our predictions and the overall process. The early screens are done with simple biochemical tests.

“Once we have filtered through the original list, we will run through additional iterations and make modifications to the structures to improve activity and drug-like properties,” Manuso says. “Since we are focusing on a relatively small number of compounds at this point, we will utilize low throughput assays with a high level of disease relevance. This is to ensure that our candidates are likely to have the properties that make good drugs such as high permeability, metabolic stability and good pharmacokinetic characteristics.”

He adds that as these tests progress there could be one of three results: none of the drugs worked, some do in a refined and final way, and some do, but need to be optimized.

“In total, the results of these first tests give clues as to what the next iteration of development should be,” says Manuso. “We make sure that the candidate that we end up with is the most likely, optimal candidate.”

He adds, “This is not a push button process. This requires a lot of intelligence.”

The intelligence he is referring to comes in two packages – computer-based and human.

On the computer side, the company uses a proprietary master software system that is able to run approximately 30 programs underneath it in such a way as to make sure the company is correctly modeling the cancer target and optimizing the selection of drugs to test.

Since the process runs on large amounts of information, the system is also designed to ensure that the information is available real time to the end user, so that the best decisions can rapidly be made as to the next compounds to test and in what system.

Running these computers and overseeing how models and drugs are processed through the system necessitates exper-ienced and highly educated chemists and biologists.

According to Manuso, the company requires a biologist and chemist to work together on models and tests at all times because each discipline is only one-half of the expertise needed to gain a complete picture of a drug and its effectiveness.

“If you were in that room, you would see a battery of computer monitors on the wall with multiple models of the cancer target, and chemists and biologists working with potential molecules to optimize the interactions between compounds and the target,” says Manuso.

“It looks a lot like a videogame, but I don’t want to under sell or under project the importance of human intelligence in this process,” Manuso says. “These are neat tools, but we have to have very talented people to make these decisions on how to move the process forward.”

He goes on to add, “This process — the CLIMB process — compresses the total time to develop a target drug selection to generally two or less years. Generally, for other companies, this time could be as long as seven years.”

Manuso then explains that the company does not do the research to develop the cancer targets. He says it is far more practical to leave that level of research up to universities and larger companies.

“We continuously monitor emerging biology to identify biological targets,” he explains. “Since our process is very rapid, we are not required to internally search for targets to get a head start before our competitors initiate a program in the same target space. We utilize RSS feeds and web crawlers to constantly collect information for us, in order to maintain a comprehensive understanding of biological targets - both current and targets which we may want to develop inhibitors for” he says.

According to Manuso, the number of potential drugs and cancer targets is immense. For the latter, targets are measured in the tens of thousands; while for the former, the drug space is in the area of the tenth to the sixty-second power. These are huge numbers that require the company to be very focused on how it approaches matching drugs to cancer targets.

Manuso says SuperGen has target product profiles which include approximately 30 attributes that a candidate must meet before it progresses from discovery to development. Most of these attributes are based on characteristics of successful drugs.

He adds that SuperGen has distinguished itself from competitors by developing a large computer-based library of structures, which increases the probability the company will be able to come up with effective candidate drugs and that these structures are novel and in clean intellectual property space.

“You can have an immense number of chemical structures in your database, but without the criteria and proprietary algorithms to search and select them you will be lost and in a state of confusion,” says Manuso. “What we have is the selection criteria to make more intelligent selections within the library that exists.”

Looking forward, Manuso says the company will seek to grow its revenues through continued research of new drugs while working to decrease the time it takes to develop them.

“We want to focus on new drug targets that are relevant to the treatment of cancer and use CLIMB to stay ahead of our competitors,” he says.