We are studying the influence of small structural changes to ATP-competitive kinase inhibitor scaffolds on binding mode and kinome-selectivity profile. To this end, we have developed synthetic routes to focused libraries of fragment-like molecules that comprise small structural modifications along multiple vectors of a single scaffold. We have investigated structure-selectivity profiles by biochemical screening (Caliper Profiler Pro� assay) and binding modes by X-ray crystallography. We anticipate that this knowledge can be applied to other kinase inhibitor scaffolds of interest, potentially accelerating the hit-to-lead phase of kinase chemical probe and drug discovery projects, and may contribute to the design of novel hinge-binding scaffolds.We initially chose to investigate the imidazo[4,5-b]pyridine hinge-binding scaffold which has been elaborated in-house to give potent, orally bioavailable inhibitors of Aurora A kinase, and dual FLT3/Aurora kinase inhibitors for the treatment of Acute Myeloid Leukaemia. We will present synthetic methodology compatible with flexible elaboration along multiple vectors of the imidazo[4,5-b]pyridine scaffold, including the discovery of efficient direct arylation methods for C2 functionalisation and its incorporation into fragment-like multi-vector libraries.Our results demonstrate that small changes to kinase hinge-binding motifs can have dramatic effects on both selectivity and kinase binding mode. We will present our profiling results and analysis of kinome selectivity patterns with reference to both kinase primary sequence and to protein-structural information. The extent to which the observed trends are replicated in alternative hinge-binding motifs is currently under study and application to the design of novel hinge-binding scaffolds is underway in our laboratories.

Synthesis & kinome selectivity patterns of imidazo[4,5-<i>b</i>]pyridine-derived fragment libraries

248th National Meeting (2014)

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Synthesis & kinome selectivity patterns of imidazo[4,5-b]pyridine-derived fragment libraries