A fragment-based selection approach for the discovery of peptide macrocycles targeting protein kinases

Protein kinases are implicated in diverse signaling cascades and have been targeted with small molecules that typically bind the conserved ATP-binding active site. These inhibitors are often promiscuous and target multiple protein kinases, which has led to the development of alternate strategies to discover selective ligands. We have recently described a fragment-based selection approach, where a small-molecule warhead can be non-covalently tethered to a phage-displayed library of cyclic peptides. This approach led to the conversion of the promiscuous kinase inhibitor, staurosporine, into a selective bivalent inhibitor.