Fragment ligated inhibitors selective for the polo box domain of PLK1
Methods for developing non-peptidic inhibitors that target the polo-box domain of PLK1 proteins are described. Methods include developing structure activity relationships for peptidic inhibitors followed by development of non-peptide fragment alternatives for portions of the peptide inhibitors. The non-peptide fragment can provide similar structure activity relationship as the replaced peptide. Fragment alternatives to key binding determinants are identified in an iterative computational and synthetic process facilitated through understanding of the peptide structure-activity relationships. The approach is informed by peptide structure-activity data obtained through synthesis and testing of truncated and mutated analogs of known PBD binding motifs.
1. A fragment ligated inhibitor that is selective to a polo box domain of a PLK1 protein, the fragment ligated inhibitor comprising a peptide fragment and a non-peptide fragment, the peptide fragment comprising S[pT]PNGL (SEQ ID NO: 12), LLCS[pT]AI (SEQ ID NO: 23), S[pT]AI (SEQ ID NO: 24) or S[pT]A (SEQ ID NO: 25), the peptide fragment including no additional peptide residues on the N-terminus of the peptide fragment, the non-peptide fragment comprising a 4-alkyl benzoic acid, a 4-alkylthio benzoic acid, a 4-alkylamino benzoic acid, or a 4-alkoxy benzoic acid, wherein the non-peptide fragment is directly bonded to the N-terminus of the peptide fragment.
2. The fragment ligated inhibitor according to claim 1 , wherein the non-peptide fragment comprises an unsubstituted alkyl group.
3. The fragment ligated inhibitor according to claim 2 , wherein the non-peptide fragment comprises an unsubstituted straight chain alkyl group.
4. The fragment ligated inhibitor according to claim 1 , wherein the non-peptide fragment comprises ethyl-benzoic acid, propyl benzoic acid, or butyl-benzoic acid.
5. The fragment ligated inhibitor according to claim 1 , wherein the non-peptide fragment comprises propylamino benzoic acid, methylamino benzoic acid, methylthio benzoic acid, ethyoxy benzoic acid, or propoxy benzoic acid.