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This version was published on March 1, 2007
Journal of Biomolecular Screening, Vol. 12, No. 2, 159-166 (2007)
DOI: 10.1177/1087057106297787

A Novel Platform for Accelerated Pharmacodynamic Profiling for Lead Optimization of Anticancer Drug Candidates

Jeffrey Szwaya

Charles Bruseo

Enkeleda Nakuci

Denise McSweeney

Department of Molecular Oncology, ArQule, Inc., Woburn, MA

Xiaoqin Xiang

Department of Molecular Oncology, ArQule, Inc., Woburn, MA; Oncology Disease Area, Novartis Institutes for BioMedical Research, Cambridge, MA

David Senator

Dennis France

Chang-Rung Chen

Department of Molecular Oncology, ArQule, Inc., Woburn, MA

Oncology drug discovery is, by definition, a target-rich enterprise. High-throughput screening (HTS) laboratories have supported a wide array of molecularly targeted and chemical genomic approaches for anticancer lead generation, and the number of hits emerging from such campaigns has increased dramatically. Although automation of HTS processes has eliminated primary screening as a bottleneck, the demands on secondary screening in appropriate cell-based assays have increased concomitantly with the numbers of hits delivered to therapeutic area laboratories. The authors describe herein the implementation of a novel platform using off-the-shelf solutions that have allowed them to efficiently characterize hundreds of HTS hits using a palette of Western blot–based pharmacodynamic assays. The platform employs a combination of a flatbed bufferless SDS-PAGE system, a dry ultra-rapid electroblotting apparatus, and a highly sensitive and quantitative infrared imaging system. Cumulatively, this platform has significantly reduced the cycle time for HTS hit evaluation. In addition, the routine use of this platform has resulted in higher quality data that have allowed the development of structure-activity databases that have tangibly improved lead optimization. The authors describe in detail the application of this platform, designated the Accelerated Pharmaco-Dynamic Profiler (APDP), to the annotation of inhibitors of 2 attractive oncology targets, BRAF kinase and Hsp90.

Key Words: oncology • Western blotting • infrared imager • cell-based profiling assays • Hsp90 • BRAF kinase


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