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IN A REAL BIND:
On the left, a BH3 peptide model bound to Bcl-2 protein. On the
right, Infinity Bcl-2 inhibitors occupying parts of
that binding groove. |
When Infinity Pharmaceuticals and Novartis signed a deal potentially worth $400 million in March of this year, it wasn't just the size of the agreement that drew attention, but the target involved. With an upfront payment of $30 million and promises of milestones down the road, Novartis put dibs on compounds inhibiting Bcl-2
-- one of the most attractive but intractable target families in the apoptosis pathway. Infinity claims its unique chemistry platform has helped uncover good antagonists of Bcl-2 and related proteins. But Infinity is not the only company claiming breakthroughs on the cell death front. Suddenly, a whole new generation of apoptosis-targeting drugs is coursing into
trials.
It's not surprising there's so much attention on the cell death switch.
"What is particularly nefarious about cancer cells is that they refuse to die and can survive in noxious environments," says Julian Adams, president and chief scientific officer of Infinity. Even worse,
"Most of those cells are not dying but they are not dividing either," he says. So, drugs targeting cell division aren't going to hurt
them.
Targets abound: Besides Bcl-2, there's p53, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), IAPs (inhibitors of apoptosis proteins), and a growing list of others. There's even a new holistic approach.
"When we started to think about cell cycle as a target in the early Ô90s, we were thinking about individual targets," says Millennium Pharmaceuticals' Mark Rolfe, vice president in oncology discovery.
"Now, we think about pathways, and thanks to new technology, we can integrate much of what we know."
Another inspiration is Velcade (Millennium's bortezomib), the world's first official apoptosis inducer. Velcade stops proteasomes from degrading certain proteins. The buildup of those proteins then kick-starts apoptosis in the cancer cells.
"By Ôtaking out' specific kinases, ubiquitin ligases, or subgroups of proteasome substrates, we hope to get more therapeutic effect and less toxicity," says
Rolfe.
Velcade is currently FDA-approved as a second line therapy for multiple myeloma. The drug has already ratcheted sales of more than $140 million in 2004 and $192 million in 2005. Millennium anticipates 17 percent to 30 percent growth in sales for 2006, and the drug is in trials for a number of other
cancers.
While Velcade proves the proteasome's importance, the rest of these targets still have to be validated, and that might not be easy. For example, the cyclin-dependent kinase (CDK) inhibitors that originally inspired the field have made barely any progress despite 20 years of
work.
Bcl-2 has also been hard to nail down. Groundbreaking science showed it's a critical cell death inhibitor and made Bcl-2 the most popular apoptosis-related target of all. After 10 years in development, Genta's Genasense (oblimersen) is up for approval now both in the United States and Europe. (See
"Clinical Connection," page 14.) But it's not certain Genasense, an antisense oligonucleotide targeting Bcl-2, will get approved. The FDA rejected the company's 2003 application to market the drug for treatment of melanoma. Indeed, it's not even clear how much of Genasense's activity is attributable to Bcl-2 inhibition.
"We could have a whole discussion whether Genasense acts via Bcl-2," Rolfe
says.
Like CDKs, the Bcl-2 family proteins present challenging targets. Infinity's answer to that is novel chemistry.
"We are making more complex molecules, inspired by those from nature," says Adams.
"So we can interrogate much more complex targets, such as protein-protein interactions." The Bcl-2 proteins block apoptosis by interacting with each other. In doing so, they form a large surface that is awkward to hit with small
molecules.
Velcade Paves the
Way
Having invented Velcade and worked on its development first at ProScript and then at Millennium (which acquired ProScript), Adams is enthusiastic about now heading the Infinity program because Bcl-2 is not just a factor, but
"critical" to the survival of certain cancer types, such as follicular lymphoma. Infinity has also been able to move relatively quickly, in about three years, from target to candidate drugs.
"Only Abbott and Infinity have potent Bcl-2 inhibitors," Adams says. Abbott's (ABT-737) was designed using a novel structure-based approach developed there. Interestingly, the Abbott and Infinity compounds have very different chemistries, according to
Adams.
Millennium, meanwhile, is also ready to build on Velcade's success. The company has made a major investment in animal models, apoptosis reagents, and imaging. Key tools, including biomarkers, are used first in discovery and then handed over for trials. Researchers determine early on whether:
"We've inhibited the target inside the patient, and does that lead to an important downstream event, and does that event correlate to a tumor response," says
Rolfe.
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“By ‘taking out’ specific
kinases, ubiquitin ligases, or subgroups of proteasome
substrates, we hope to get more therapeutic effect
and less toxicity.”
MARK ROLFE,
MILLENNIUM PHARMACEUTICALS |
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For example, Millennium has a kinase inhibitor targeting Aurora A. One of that kinase's key activities is to autophosphorylate itself at the amino acid threonine 288. Millennium researchers started early developing a monoclonal antibody (MAb) directed precisely to that site. Now, the company is using that MAb to check whether tissue samples from treated patients show that the drug is causing the expected effects. It can take up to a year to make such MAbs, and they don't always work in the end. So,
"The MAb was being developed in tandem with the drug," says
Rolfe.
This next wave of apoptosis inducers seems particularly promising, but it will take several years for any of these new approaches to reach the critical later phases. Infinity/Novartis and Abbott's Bcl-2 inhibitors are all still in preclinical stages. Meanwhile, Millennium's Aurora kinase inhibitor is in Phase I. The company also has a FLT-3 inhibitor in Phase
II.
Plenty of interesting apoptosis inducers are in late stages, too. With so many candidates, it would be surprising if apoptosis inducers don't become a major factor in future cancer care.
"Optimistically, I would expect consistent approvals in the next five years," Rolfe says. Those companies doing trials will be looking at more than just new targets, but also trying to better understand when and how to use these drugs. According to Rolfe, these drugs will starts as combination therapies with chemotherapeutics and angiogenesis
inhibitors.
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