Several members of the Src family kinases are associated with cellular dysfunctions including cancer. Drugging the kinase domain (ATP binding site) in these enzymes has proven to have high levels of cross-reactivity with other family members. We propose targeting SH3 domains of Src family kinases as an alternative drugging site. The SH3 domain is involved in regulation of activity of these enzymes. Starting from a poly-proline peptide ligand with modest binding affinity (Kd ~ 1 μM) across Src family SH3 domains we were able to arrive at highly potent inhibitor for SH3 domain of Lyn kinase (Kd = 6 nM, over two orders of magnitude increase in binding affinity) by placing a rhodium(II) core on the peptide. The observed high affinity and selectivity towards Lyn SH3 stems from interaction of peptide-bound rhodium(II) core with two unique histidine residues at periphery of peptide binding site, which has a synergistic effect and increases affinity. Using available structural data on SH3 domains we can tune specificity of metalloinhibitors by varying the placement of rhodium(II) core along peptide to allow rhodium(II) to interact with unique Lewis base (histidine, methionine, cysteine) residues of SH3 domains of other Src family kinases. This rational design strategy allowed preparation of another highly selective nanomolar binder towards SH3 domain of related kinase, Lck ( Kd = 79 nM).

Highly potent and selective metalloinhibitors for SH3 domains based on rhodium(II) metallopeptides

249th National Meeting (2015)

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