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From lab bench to board room: UB chemist's approach to anti-cancer compounds makes the leap
By ELLEN GOLDBAUM
Contributing Editor
In a classic example of scientific research that has successfully outgrown the university lab where it was born, a UB professor's unique method for designing and synthesizing anti-cancer compounds, called protein kinase inhibitors, is being commercialized.
HANGAUER
Kinex Pharmaceuticals, LLC, a UB faculty start-up company that has attracted the participation of some major players in the pharmaceutical industry, now has an exclusive option to license the professor's technology from the university and UB has filed two international patents on the new approach.
The technology is behind what may be the next generation of protein kinase inhibitors, a multi-billion-dollar market also being pursued vigorously by big pharma.
According to Kinex officials, the company expects to have compounds in human trials within two years.
"We are focusing our strategy on developing drugs that shrink tumors and prevent metastases with minimal or no side effects," said David Hangauer, associate professor of medicinal chemistry in the Department of Chemistry, College of Arts and Sciences, who developed the technology and the resulting protein kinase inhibitors.
"For the broad range of cancers we are targeting, there are no good therapies out there with minimal side effects," he said.
The key advantage of the new protein kinase inhibitors that Kinex is developing is that because of the unique binding site against which these compounds are targeted, there is a greatly reduced chance that patients will develop resistance to these drugs—a problem that already has rendered ineffective some of the first marketed protein kinase inhibitors.
"For a drug that patients will take for the rest of their lives, resistance is a huge issue," said Hangauer, who also is Kinex's vice president for research and development, "particularly because the cancer genome is unstable and it mutates very quickly."
The drugs that are developed using this approach also will be more selective than the currently marketed protein kinase inhibitors because Hangauer chose to pursue a binding site that is designed by nature to accept as substrates only proteins specific to this enzyme. Other companies are pursuing a site that binds ATP, a substrate that is ubiquitous for all 1,000 protein kinases in the body.
"Even if the enzyme mutates our binding site, thereby preventing the drug from binding there, its natural substrates also will not be able to bind there," explained Hangauer. "The result still will be cancer cells that cannot grow and spread to other parts of the body."
The prospect of being able to avoid the development of resistance is powerful testimony to the potential of this approach to obtaining protein kinase inhibitors as cancer drugs, according to Allen Barnett, chief executive officer of Kinex Pharmaceuticals, who formerly was vice president of technology acquisition and external collaborations of the Schering-Plough Research Institute.
"This is the way that people will be designing protein kinase inhibitors in the future, if we are successful," said Barnett, who was responsible for evaluating and developing several multi-billion dollar drugs, including Claritin, at Schering-Plough.
"David's work has reached the stage where the basic technology is in place and no new discoveries are needed," he said. "He has the target, he has the lead compounds, they work selectively, they don't hit other targets. The next step is to convert it into a real drug."
That involves improving potency, doing animal and pharmacokinetic studies and developing more compounds around the initial leads—activities that are not covered by research grants, Barnett explained, which is why the company now is approaching the investor community, both locally and nationally.
"Right now, I view this as a scale-up project," said Barnett.
Protein kinases are enzymes that catalyze important chemical reactions, called phosphorylation, in cells and some of them are critical for the survival of cancer cells but unnecessary for normal cells.
Right now, researchers throughout the pharmaceutical industry and academia are developing anti-cancer drugs against various protein kinases and one of them, called Src, has emerged as one of the most promising.
While some major pharmaceutical companies are pursuing inhibitors of this enzyme, the approach Hangauer has taken to target Src demonstrates unique advantages.
"We used our proprietary process to target our drugs to a different binding site on this particular enzyme," he said. "We decided early on that going after this particular binding site would put us ahead of the game."
So far, that strategy has proven successful, with screening tests in tumor cells at the National Cancer Institute, as well as in the Roswell Park Cancer Institute laboratories of Ralph J. Bernacki of the Department of Pharmacology and Therapeutics, and Thomas Nicotera of the Department of Molecular and Cellular Biophysics showing that Hangauer's compounds have activity against all of the major cancers, including those for which current drugs are not very effective, such as lung cancer, highly metastatic prostate cancer, colon cancer and ovarian cancer.
Hangauer's protein kinase inhibitors also are showing significant promise in preventing noise-induced hearing loss in collaborative research with Donald Henderson, professor in the Department of Communicative Disorders and Sciences and director of UB's Center for Hearing and Deafness, and Nicotera, who is adjunct associate professor in the same department.
And while the resistance issue is probably Kinex's most powerful advantage over other protein kinase inhibitors for treating cancer, the high selectivity of its compounds, Hangauer said, also greatly reduces the severity of potential side effects.
In some cases, he noted, the effective dose could be as much as 100 times less drug than the protein kinase inhibitors now on the market.
Barnett noted that the same basic approach Hangauer has used to develop the anti-cancer compounds also could be used to attack other enzymes in the same class and to target other diseases.
This new class of compounds has shown activity against enzymes involved in a broad range of other diseases and conditions, including Type II diabetes, autoimmune diseases, osteoporosis, stroke and psoriasis.
"To me, the decision about establishing a company is based on whether or not there is something lasting," Barnett said. "If there's just one deal or one product, then you don't need to develop a company; but if you're talking about something that potentially is useful for other types of drugs and classes of drugs, and can lead to a pipeline of products, then that's the basis of a business, and that's what I see in Kinex."
In applying for the broadest possible patent protection on Kinex's technology and compounds, UB also has made a significant commitment to the company.
"Kinex has an excellent platform for development of a new class of drugs with great potential in cancer therapy and for other diseases," said Robert Genco, vice provost for the Office of Science, Technology and Economic Outreach and SUNY Distinguished Professor in the Department of Oral Biology, School of Dental Medicine. "The company has an excellent management team: company CEO Dr. Barnett is experienced in drug development and Dr. Hangauer is a committed and very talented scientist."
While it will be several years before Kinex is able to get a product to market, Genco added that the company has good intellectual property protection.
"The main elements for success are in place," he said.
In addition to Barnett, Johnson Y. N. Lau, formerly chairman and chief executive officer of Ribapharm, Inc., who took that company public in one of the largest biotech initial public offerings ever, is executive chairman of Kinex Pharmaceuticals.
Lyn Dyster, who successfully founded the biotech firm GenCyte, is Kinex's vice president for operations and business development.