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June 01, 2009 (Vol. 29, No. 11)

Ambit Has High Hopes for Kinase Screening Tool

Firm’s KINOMEscan Measures the Active Site of the Enzyme rather than the Activity

  • Flexible High-Throughput Platform

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    Selectivity scores calculated for binding interactions with Kd<3 µM using KINOMEscan assay platform.

    The success of AC220 also validates Ambit’s KINOMEscan™ profiling and drug-optimization platform. AC220 was identified using KINOMEscan, and it was designed, synthesized, screened, characterized, and optimized at Ambit. KINOMEscan is an active-site dependent, competition binding assay in which human kinases of interest are tagged with DNA, and a known ligand is immobilized on a solid support. Using real-time quantitative PCR, the amount of kinase bound to the immobilized ligand is measured in the presence and absence of a test compound. KINOMEscan includes a growing panel of more than 400 kinases, including all known clinically relevant kinases and mutations and inactive forms.

    The technology replaces slow and time-consuming enzyme activity assays for evaluating potential kinase inhibitors. KINOMEscan consists of a set of HTS assays that measure binding at the active site of an enzyme, rather than enzyme activity. The degree of binding near the active site approximates the extent of inhibition of enzyme activity. “It took us a few years to broadly confirm that binding was a substitute for enzyme inhibition,” continues Salka. The assay is now widely accepted by drug discovery researchers, he adds.

  • Profiling Data

    Ambit scientists published kinase profiling data for 38 well-known kinase inhibitors in January 2008, including details of a novel approach for quantifying the interactions between compounds and the human kinome. The approach allows for the systematic analysis of high-throughput kinase-profiling data and dramatically improves the efficiency of selecting and optimizing high-quality drug candidates from kinase-based compound libraries.

    About 100 clients have contracted with Ambit to screen samples with KINOMEscan, including Roche, Cephalon, Astra-Zeneca, and Bristol-Myers Squibb, Salka reports. Customers send molecules of interest to Ambit, and a report is generated in one to two weeks.

    “Many compounds at biotechnology and pharmaceutical companies that are moving their way through clinical development were selected and optimized with KINOMEscan,” Salka says. The process is flexible—customers can scan one compound against one kinase assay or 10,000 compounds against all 442 assays included in the HTS platform.

    Rounding out Ambit’s in-house pipeline is AC480, a panHER kinase inhibitor for solid tumors in Phase II trials. By mid-2009, Ambit hopes to extend the testing of AC480 to glioblastoma patients. A BRAF kinase inhibitor was developed in partnership with Cephalon. Many tumors show mutations in the BRAF kinase, including melanoma and colon tumors. Inhibitors of Aurora, JAK2, and CSF1R kinases are also in development for inflammatory diseases and various types of cancers.

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