Fragment ligated inhibitors selective for the polo box domain of PLK1

A method for developing a fragment ligated inhibitor that is selective for a polo box domain of a PLK1 protein, the method comprising iteratively replacing amino acid residues of a peptide polo box domain selective PLK1 inhibitor, the amino acid residues being replaced by a method comprising:

• identifying a first fragment of the peptide polo box domain selective PLK1 inhibitor for replacement has upon a structure activity relationship of the peptide polo box domain selective PLK1 inhibitor, the first fragment including one or more of the amino acid residues;
• computationally docking a first non-peptide fragment into a volume of a binding site of the PLK1 protein, the binding site being known to interact with the first fragment of the peptide polo box domain selective PLK1 inhibitor;
• computationally docking a second non-peptide fragment into the volume of the binding site of the PLK1 protein;
• scoring the first non-peptide fragment and the second non-peptide fragment through energetic and geometric evaluation of docked poses of the non-peptide fragments;
• selecting one of the first non-peptide fragment and the second non-peptide fragment based upon the scores thus obtained;
• replacing through chemical synthesis the first fragment of the peptide polo box domain selective PLK1 inhibitor with the selected non-peptide fragment to form a first fragment ligated inhibitor;
• assaying the first fragment ligated inhibitor in vitro to obtain data concerning the first fragment ligated inhibitor;
• developing a second generation non-peptide fragment derivative of the selected non-peptide fragment;
• computationally docking the second generation non-peptide fragment derivative into the volume of the binding site of the PLK1 protein;
• scoring the second generation non-peptide fragment derivative through energetic and geometric evaluation of docked poses of the second generation non-peptide fragment derivative;
• replacing the selected non-peptide fragment of the first fragment ligated inhibitor with the second generation non-peptide fragment derivative to form a second generation fragment ligated inhibitor;
• assaying the second generation fragment ligated inhibitor in vitro to obtain data concerning the second generation fragment ligated inhibitor;
• and
• replacing at least one additional fragment of the peptide polo box domain selective PLK1 inhibitor with at least one additional non-peptide fragment, the at least one additional fragment of the peptide polo box domain selective PLK1 inhibitor including one or more amino acid residues of the peptide polo box domain selective PLK1 inhibitor, the first fragment and the at least one additional fragment being different fragments of the peptide polo box domain selective PLK1 inhibitor.