Study Uses Ambit's Novel Kinase Profiling Technology to Analyze 20 Kinase Inhibitors

02/14/05 -- Ambit Biosciences today announced the publication of data obtained by applying the company's novel kinase profiling technology to 20 compounds including Gleevec®, IRESSA®, TARCEVA(TM) and a number of kinase inhibitors currently in clinical trials. The study, which evaluated the specificity of these compounds and revealed potential new uses for some, was published in an article entitled "A Small Molecule-Kinase Interaction Map for Clinical Kinase Inhibitors" (Miles A. Fabian, et. al.) in the March issue of Nature Biotechnology (DOI number: 10.1038/nbt1068), currently available online.

"Kinases play key roles in cancer, inflammation, diabetes and other diseases, making kinase inhibitors one of the most important drug classes," explained David J. Lockhart, Ph.D., President and Chief Scientific Officer of Ambit Biosciences. "Ambit's novel technology allows us to quickly and efficiently test kinase inhibitors against nearly 200 kinases at once, revealing how well the compounds bind to their intended targets and exposing `off-target' binding that may be responsible for side-effects or that might even reveal unforeseen opportunities to use the compounds to treat other diseases."

The paper describes Ambit's kinase profiling technology and outlines data generated by profiling 20 kinase inhibitors, many of which are either FDA-approved or in clinical development, across a panel of 119 kinases. Highlights of these findings include:

• Gleevec, marketed by Novartis Pharmaceuticals Corporation for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST), was found to bind tightly to a kinase known as LCK, a key regulator of T-cell maturation and activation, indicating that Gleevec or close derivatives may be clinically useful as an immunosuppressant.

• BIRB-796, until recently in clinical trials with Boehringer Ingelheim Pharmaceuticals for the treatment of various inflammatory and autoimmune diseases, was found to bind tightly to a Gleevec-resistant form of the kinase ABL (T3151), the toughest of the Gleevec-resistant mutations, indicating that BIRB-796 or close derivatives may have the potential to treat Gleevec-resistant cancers.

• Recent data have indicated that only some patients respond to treatment with IRESSA, marketed by AstraZeneca for the treatment of non-small-cell lung cancer, and that response may be linked to certain mutations in the kinase known as EGFR. Ambit found that IRESSA and other compounds that target EGFR such as TARCEVA, PKI-166, SU-11464 and GW-2016 all bind tightly to wild-type (normal) EGFR and each of the nine mutant forms of EGFR tested with similar affinity, indicating that these mutations do not enhance the ability of the compounds to bind EGFR and that there must be other causes for the increased response in certain patient groups.

• Compounds such as Gleevec, GW-2016 and Vatalanib (PTK-787) bind few kinases other than their primary targets, while compounds such as SU11248, SP600125, EKB-569 and ZD-6474 bind a host of other kinases, in some cases with a strength similar to that with which they bind their primary targets.

"The publication of this paper in Nature Biotechnology, along with our existing collaborations with Bristol-Myers Squibb Company, GlaxoSmithKline, Pfizer and Roche, provides validation of the utility of Ambit's novel kinase profiling technology," said Scott Salka, Chief Executive Officer of Ambit. "We are confident that our approach fundamentally improves upon conventional methods for the discovery and development of kinase inhibitors, a very important class of drugs, by providing information that can be used to create more effective drugs with fewer side effects. We are also using our own technology to discover and develop drugs internally, the first of which we expect to enter the clinic later this year."

The paper also describes Ambit's novel kinase profiling technology, a new and efficient way to evaluate kinase-inhibiting compounds by testing them simultaneously against a large number of human kinases. By testing compounds against large numbers of kinases at once, including mutant forms of many kinases, the technology can illustrate the specificity with which molecules bind their targets and determine if compounds bind additional kinases that could cause side effects or lead to new therapeutic uses.

"The data obtained by applying Ambit's kinase profiling technology to the study of these compounds provide a critical foundation for a deeper understanding of kinase inhibitor activity and design," Lockhart added. "These results have direct and immediate implications for current clinical practice, kinase inhibitor drug development, chemical genetics and kinase structural biology studies, and we hope that they help accelerate the development of new drugs in this important class."

About Ambit Biosciences

Ambit Biosciences is a privately-held biopharmaceutical company developing small molecule neuroprotectants for the treatment of stroke and other CNS disorders and kinase inhibitors for the treatment of cancer and inflammation. Ambit plans to initiate clinical trials for stroke in 2005 and oncology in early 2006. Ambit's proprietary technology, which has been validated through collaborations with Bristol-Myers Squibb Company, GlaxoSmithKline, Pfizer and Roche, provides an unprecedented ability to identify, characterize, and quantify protein-small molecule interactions. Ambit has raised a total of nearly $50 million from investors including Perseus-Soros Biopharmaceutical Fund, Forward Ventures, Roche, Avalon Ventures and GIMV NV.

Source: Ambit Biosciences