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Horizon Discovery
Horizon Discovery

SU11248: Genesis of a New Cancer Drug

Every drug has a story behind it.

By | April 11, 2005

<p>STRUCTURALLY BOUND:</p>

© 1997 AAAS

Crystal structure of ATP binding site of FGFR1 in complex with SU5402. Molecular surface representation (bottom) and a backbone representation (top) of the same view showing superposition of SU5042 (green) and ATP (yellow) in complex with the kinase domain of FGFR1. Both surface and backbone representations colored purple represent atoms of the hinge region, light blue for atoms of the nucleotide-binding loop and yellow for atoms of the catalytic loop. (From M. Mohammadi et al., Science, 276:955–60, 1997)

Every drug has a story behind it. Here, I condense 25 years of hard work by hundreds of people by focusing on key events and characters that shaped the discovery of SU11248, a new cancer drug. Cancers remain an immense problem, but this story has an affirmative message: Investment in basic research, the mining of that research for promising leads, and the relentless, dedicated development of these leads can yield new therapies.

In the early 1980's multiple areas of basic research in biology and medicine converged, setting the groundwork for two decades of frenzied discovery on the molecular mechanisms underlying many human cancers.1 Such discoveries depended upon developments in molecular biology, including powerful DNA cloning and sequencing methods; protein expression and purification technologies; and the microsequencing of minute amounts of peptides, which were key to unveiling basic cellular mechanisms. In addition, the genetic analyses of human cancers, combined with genetic studies in mice, worms, and fruit flies, provided a consistent view of the key components that govern cell proliferation, differentiation, metabolism, cell cycle, and cell survival.

It became apparent that an important cause of cancer's uncontrolled proliferation is the subversion of processes stimulated by the binding of growth factors such as EGF, PDGF, and SCF to the family of cell-surface receptors known as receptor tyrosine kinases (RTKs).2 A large group of cytoplasmic protein tyrosine kinases (PTKs) similarly plays an important role in mediating cellular signals induced by various extracellular cues. And aberrant activation of PTKs and their intracellular signaling pathways is a hallmark of, and critical mechanism for, oncogenic cell transformation.34

In 1986 Umezawa and colleagues discovered the first PTK inhibitor of the epidermal growth factor receptor.5 EGFR and additional PTK inhibitors were subsequently tested for their ability to interfere with enzymatic PTK activity and to block cell proliferation and oncogenesis.6

THE SUGEN STORY

<p>Joseph Schlessinger</p>

Sugen was founded in 1991 to develop anticancer drugs that target dysfunctional protein kinases, phosphatases, and intracellular signaling pathways. The first company to attempt this, Sugen was a partnership between my laboratory at New York University (NYU) Medical School and Axel Ullrich's lab at the Max Planck Institute (MPI) for Biochemistry in Martinsried, Germany. The third cofounder, Stephen Evans-Freke, became chair and CEO, while Ullrich and I assumed the positions of co-chief scientists.

The company was established in Redwood City, Calif., and Peter Hirth, from Boehringer Mannheim, joined to build a team comprising biologists, chemists, biochemists, and clinicians. With conceptual foundations, intellectual property, materials, and experimental approaches developed at our laboratories at NYU and MPI, Sugen created contracts between the company and the founding academic institutions, including research support, equity stake, and royalty payments on any Sugen-developed drugs.

Although Sugen invested significant resources into the search for novel kinases and phosphatases and into cell-signaling research, our main goal was to identify new families of PTK inhibitors to treat cancers and other diseases caused by tyrosine kinase dysfunctions. The lion's share of inhibitors that we and others found interfered with ATP binding within the catalytic core of the enzymes. Most pharmaceutical companies reacted with skepticism. Many argued that drugs that prevent binding at the nucleotide-binding site would likely exhibit serious adverse effects and toxicity. They anticipated that our ATP antagonists would bind many cellular protein kinases and a variety of other ATP-binding proteins. They also maintained that the high concentration of ATP in cells would limit the utility of ATP antagonists.

But biochemical experiments, studies with cultured cells, and structural analyses told us otherwise. It became clear that the structural diversity of the ATP-binding pocket provides an excellent opportunity for generating inhibitors with good selectivity towards a variety of protein kinases. Furthermore, many PTK inhibitors exhibited tolerable side effects in preclinical experiments and in Phase I clinical trials.

Several series of novel PTK inhibitors were developed at Sugen. The figure (at right) depicts a partial description of the evolution of PTK inhibitors that led to the discovery of SU11248. A series of oxindole-based compounds were prepared and characterized using biochemical assays followed by comparison of their inhibitory activity in cell culture. The availability of the crystal structure of SU5402 and SU6668 in complex with the PTK domain of FGFRI,78 combined with modeling and iterative analyses of the activity of a series of compounds, facilitated the discovery of SU5416, SU11248, and SU11657 (not pictured).

In 1999, Pharmacia acquired Sugen, and Peter Hirth became the company president. In a joint effort with other Pharmacia sites, Sugen embarked on clinical trials in colon cancer with two of the angiogenesis antagonists, SU5416 and SU6668; the trials were eventually discontinued. In 2000, Pharmacia merged with the pharmaceutical division of Monsanto, and in 2003 Pfizer bought Pharmacia. As part of the reorganization, Pfizer discontinued support for Sugen and closed the laboratories. Pfizer continued to develop several Sugen drugs, however, including SU11248 and SU11657.

MULTITARGET CANCER DRUGS

The tremendous success of Gleevec910 for the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST) demonstrated that protein kinase inhibitors could successfully treat cancer. Even though its unprecedented success is largely due to inhibitory effects on the oncogenic protein BCR-ABL in CML, and on the activated form of Kit in GIST, Gleevec (STI-571) was actually initially discovered as a PDGF-receptor inhibitor.

Like Gleevec, SU11248 blocks the kinase activities of several oncogenic RTKs. It is a potent inhibitor of PDGF-receptors (Kit, a stem cell factor receptor, and VEGF-receptor), and it weakly inhibits FGF-receptors. SU11248 has both antitumor and antiangiogenesis activities. Because of the critical role of activated forms of Kit in GIST, SU11248 was tested in clinical trials in GIST, including Gleevec-resistant patients with GIST. SU11248 has also been tested in Phase II clinical trials for the treatment of renal carcinoma and, in earlier trials, for the treatment of acute myelogenous leukemia and other cancers.

On February 8, 2005, Pfizer announced that in a Phase III study, led by George Demetri of Dana-Farber Cancer Institute and Harvard Medical School, "SU11248 demonstrated efficacy and safety seven months ahead of schedule. Because of these positive results, an independent panel of experts has recommended stopping the trial. Patients who have received placebo are being given the option of switching to SU11248." SU11248 (also called Sutent) is now rapidly being readied for registration and formal approval from regulatory authorities as a novel therapy for GIST. Approval of SU11248 is anticipated sometime this year.

LESSONS LEARNED

<p>COMPOUND EVOLUTION:</p>

Courtesy of Department of Pharmacology, Yale University School of Medicine

Evolution in the development of oxindole compounds, which led to the development of SU11248 (5- [5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid [2-diethylaminoethyl]amide).

Although SU11248 has not yet been widely used outside the clinical trials, its impressive efficacy in treating GIST and Gleevec-resistant patients with GIST is reminiscent of the efficacy of Gleevec for treatment of CML and GIST. Oncologists are not accustomed to working with drugs with spectacular success rates, and it was thought that Gleevec might represent a special case. The remarkable efficacy of SU11248 disproves this notion. Furthermore, it raises confidence in compounds that block the action of key cellular components, which might be applied for the treatment of a variety of cancers.

The success also emphasizes the urgency of discovering new chemical scaffolds that could be used as a basis for treating many types of cancers. Such scaffolds could serve as new weapons in the arsenal to combat drug resistance following long-term treatment with Gleevec.11 And I believe that recently developed approaches for scaffold-based drug design12 will greatly enhance the limited number of chemical scaffolds.

It has been a privilege to work on these issues over the past three decades. Investment in basic science as a catalyst for new drug development has been vindicated, and the opportunity to discover the molecular mechanism and help develop new therapies for pernicious diseases has been both satisfying and humbling.

Joseph Schlessinger, the William H. Prusoff Professor and chair of pharmacology at Yale University School of Medicine, has authored or coauthored more than 450 articles and cofounded two biotech companies, Sugen and Plexxikon.

He can be contacted at joseph.schlessinger@yale.edu.

A complete HistCite collection of Joseph Schlessinger's papers

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