Structure-guided, Fragment-based Lead Generation for Oncology Targets

Structural GenomiX, Inc. (SGX) has combined high-throughput X-ray crystallography with a fragment-based approach to lead identification/lead optimization. FAST™ (Fragments of Active Structures) exploits crystallographic screening to detect, visualize, and identify small lead-like ligands (molecular weight 150-200, typical hit rates 1-5%) that bind productively to the target protein. Each member of the FAST™ fragment library is amenable to rapid chemical elaboration at two or three points to provide access to unrivalled chemical diversity using parallel organic synthesis. Initial lead optimization involves using knowledge of the structure of the target-fragment complex and advanced computational chemistry tools to guide synthesis of small focused linear (one-dimensional) libraries. These linearly elaborated fragments are then evaluated with in vitro biochemical assays and crystallography. Thereafter, optimal variations at each point of chemical diversity are combined to synthesize focused combinatorial (two-or three-dimensional) libraries that are again examined with assays and crystallography. (The theoretical chemical diversity of the fully elaborated FAST™ fragment library exceeds 160 million compounds.) These focused combinatorial libraries typically contain multiple novel compounds of low molecular weight (<350) that bind the target protein with low nM IC 50 values and display considerable selectivity. Finally, lead series are prioritized for further medicinal chemistry and compound advancement efforts using the results of cellular and animal model assays, in vitro and in vivo ADME and in vitro toxicology studies in concert with structural information. Application of the FAST™ fragment-based lead generation process to various oncology targets will be presented.