Due to the pivotal role of phosphorylation in many fundamental cellular processes, it is not surprising that the activities of the more than 500 distinct protein kinases in the genome are strictly regulated. Correspondingly, dysregulated kinase activity is frequently the cause or consequence of human disease, which has fueled a growing interest in developing protein kinase inhibitors as therapeutics. Indeed, in recent years, this work led to the first approvals of protein kinase inhibitors for clinical use (e.g., imatinib mesylate, also known as Gleevec™).

In addition to the usual hurdles facing any small molecule drug discovery program (e.g., optimizing appropriate physical and pharmacological properties), a major challenge facing kinase programs is obtaining selectivity among the kinase family.

At GNF, our scientists have taken two approaches to this problem. We are identifying allosteric modulators that interact at sites proximal or distal to the ATP-binding site, and we are using “traditional” approaches coupled with innovative GNF technologies that create a competitive advantage in the identification of selective inhibitors. These traditional approaches include broad screening to identify novel scaffolds, focused screening of kinase-directed combinatorial libraries, and “back-screening” of GNF kinase-directed medicinal chemistry SAR collections. Among the broadly enabling technologies that GNF brings to bear in concert with these traditional approaches are x-ray crystallographic studies and structure-based design, protein NMR-guided optimization, molecular modeling, and, most recently, an industrialized system of massively parallel kinase selectivity screening using proprietary GNF automation and assay technology.

Selected Publications

• Melnick JS, Janes J, Kim S, Chang JY, Sipes DG, Gunderson D, Jarnes L, Matzen JT, Garcia ME, Hood TL, et al. An efficient rapid system for profiling the cellular activities of molecular libraries. Proc Natl Acad Sci U S A 2006;103(9):3153-8.
• Adrian FJ, Ding Q, Sim T, Velentza A, Sloan C, Liu Y, Zhang G, Hur W, Ding S, Manley P, et al. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol 2006;2(2):95-102.
• Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006;2(7):358-64.
  

Please click here for a full list of group publications