Peptide Mimetic Ligands of Polo-like Kinase 1 Polo Box Domain

Polo-like kinase 1 (Plk1) is a critical protein involved in regulation of mitosis, and aberrant expression of this kinase is found in various cancer types.  Inhibition of Plk1 is currently being pursued in pre-clinical drug development for novel anti-cancer therapeutics.  Plk1 contains an allosteric domain, known as the polo-box domain (PBD), that is responsible for localizing the kinase domain to mitotic structures through protein-protein interactions.  

This technology is an improvement and continuation of Dr. Terry Burke’s research program centered around PBD modulation. The “Plk1 PBD” portfolio focuses on compounds that disrupt Plk1-mediated protein interactions. These compounds are designed to selectively cause mitotic arrest in cancer cells with abnormal Plk1 expression by inhibiting proper localization of Plk1.  

The invention is directed to improved design and synthesis of peptidomimetic ligands that bind PBD by attaching a pivaloyloxymethyl (“POM”) group and/or by utilizing intramolecular charge masking. Invention peptides exhibit enhanced bioavailability and good efficacy. The invention also provides design and synthesis of phosphoryl-derived peptidomimetics that bind PBD.   

Related technologies within the Plk1 PBD portfolio currently consist of:

(1) E-181-2009 “Peptide Mimetic Ligands of Polo-like Kinase 1 Polo Box Domain”;
(2) E-186-2015 “Efficient synthesis of 2-amino-3-methyl-4-phosphonobutanoic acid, a phosphatase stable phosphor-amino acid analog”;
(3) E-254-2016 (closed) “Fragment-based Optimization of Ligand interactions within a key cryptic binding pocket of Plk1 PBD;
(4) E-178-2017 “Bivalent Ligands of Plk-1 that exhibit Exceptional Affinity”; and
(5) E-179-2017 “Macrocyclic Peptidomimetic of Plk-1 PBD”.

Competitive Advantages:

• Mechanism of Plk1 down-regulation is different from agents that bind at the Plk1 kinase domain ("classical kinase inhibitors")
• Due to the uniqueness of polo-box domains to the Plk family of kinases, PBD-directed inhibitors may afford selectivity advantages over classical kinase inhibitors
• Among the highest affinity Plk1 PBD-binding ligands known
• Enhanced bioavailability and good efficacy

Commercial Applications:

• Disruption of Plk1-driven cellular proliferation
• Anticancer therapies
• Complimentarity to anticancer treatment when used with Plk1 kinase inhibitors