Description:
Reference #1307: Selective Inhibition of the Polo-Like Kinase 1 PBD for Cancer Therapy
The University of South Carolina is offering licensing opportunities for the Selective Inhibition of the Polo-Like Kinase 1 PBD for Cancer Therapy.
Background:
Polo-like kinase 1 (PLK1) has been shown to be over-expressed in a number of tumors. Its expression has been demonstrated to be adversely related to prognosis, thus making it a good therapeutic target. PLK1 is comprised of two structural domains: the kinase domain, containing the ATP binding site; and the protein substrate recognition polo-box domain (PBD). Although several ATP-binding site inhibitors of PLK1 have advanced to clinical trials, there is concern about the selectivity of these compounds for PLKs isoforms. This is problematic because PLK3 has been shown to act as a tumor suppressor, and in fact might have opposing functions to PLK1. An alternative approach to developing potent and selective PLK1 inhibitors is to target the PBD.
Invention Description:
In this research, structural determinants for peptide binding to the PBDs of PLK1 have been defined, and Fragment Ligated Inhibitory Peptides (FLIPs) with improved binding have been generated. In addition, a detailed evaluation of affinity of ligands for the PBD of PLK3 has been completed and used to generate a selectivity index for PLK1, a novel analysis of true selectivity of PBD ligands.
This study validates the use of the REPLACE (Replacement with Partial Ligand Alternatives through Computational Enrichment) method to develop more drug-like small molecule PBD-inhibitors that have a high binding affinity for PLK1 while retaining selectivity against other PLKs including PLK3, a known tumor suppressor.
Potential Applications:
Overall, results demonstrate validity of targeting the PBD binding site and progress in generating more drug-like lead PBD-inhibitors that are PLK1 selective and are active against tumors resistant to ATP-inhibitors.
Advantages and Benefits:
Peptides can discriminate between the PLK family members and can therefore provide structural basis for the development of selective PLK1 inhibitory compounds.
Previous PBD peptidomimetics have required extensive modification, but these cellular studies with FLIPs demonstrate progress towards obtaining cell permeable compounds that are structurally much less complex than previously described peptidomimetics