This project targets the src homology domains of the Abl oncogene for rational anti-cancer drug design. The team consists of a partnership between my structural biology research group at the University of Colorado and a drug discovery program at OSI Pharmaceuticals. This biotechnology company has developed a series of peptidomimetic compounds as novel anticancer agents targeted at signaling domains responsible for the localization and regulation of kinases and phosphatases. My laboratory is determining the three-dimensional structures of complexes of lead compounds bound to src homology 2 (SH2) and src homology 3 (SH3) domains by nuclear magnetic resonance (NMR) spectroscopy. The specific targets are the SH2 and SH3 domains of Abl, an oncogenic tyrosine kinase for which inhibitors are in phase II clinical trials. The SH2 domain is inhibited by a pyridone derivative that mimics its natural phosphotyrosine ligand, and the SH3 domain is inhibited by spirolactam-based compound that resembles its polyproline ligands. These templates possess affinities and binding modes comparable to physiological ligands, as demonstrated by nuclear magnetic resonance spectroscopy (NMR) and surface plasmon resonance (SPR). Modifications of these lead compounds that enhance selectivity and potency will be suggested based on protein structures, NMR and SPR data, and computational modeling. Synthetic organic chemistry expertise and access to combinatorial libraries is provided by OSIP. This complementary partnership will allow the rational optimization of lead compounds with significant therapeutic potential for cancers including chronic myelogenous leukemia.
