title: Evolution and intelligent design in drug development.
abstract: Sophisticated protein kinase networks, empowering complexity in higher organisms, are also drivers of devastating diseases such as cancer. Accordingly, these enzymes have become major drug targets of the twenty-first century. However, the holy grail of designing specific kinase inhibitors aimed at specific cancers has not been found. Can new approaches in cancer drug design help win the battle with this multi-faced and quickly evolving enemy? In this perspective we discuss new strategies and ideas that were born out of a recent breakthrough in understanding the molecular basis underlying the clinical success of the cancer drug Gleevec. An "old" method, stopped-flow kinetics, combined with old enzymes, the ancestors dating back up to about billion years, provides an unexpected outlook for future intelligent design of drugs.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University Waltham, MA, USA.
authors.forename: Roman V
authors.initials: RV
authors.lastname: Agafonov
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University Waltham, MA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University Waltham, MA, USA.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Kern
keywords: Gleevec; cancer drugs; conformational selection and induced fit; drug design; evolution; protein kinases