[Development of Mid-size Bivalent Inhibitors Targeting a Cancer-related Kinase]
1Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU) (Currently known as Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo).
Abstract:
The Ser/Thr-specific kinase, polo-like kinase 1 (Plk1), is a crucial eukaryotic cell cycle regulatory protein. Overexpression of this kinase is observed in many cancer cells and where it can be related to their aggressiveness. Dysfunction of Plk1 in cancer cells causes mitotic arrest and subsequent apoptosis. Accordingly, Plk1 is considered as a target for the development of anti-cancer agents. Plk1 has two domains, a catalytic kinase domain (KD) and a polo-box domain (PBD). PBD intramolecularly interacts with its KD and regulates Plk1 activity and localization. Therefore, in addition to the KD, the PBD is considered to be a potential drug target. We have been developing peptidic low-nanomolar-affinity PBD-binding inhibitors. However, these peptides do not show significant cytotoxicity, due to their low cell membrane permeability. To obtain cell-active Plk1 inhibitors, I applied a bivalent approach designed to simultaneously engage both KD and PBD regions of Plk1 for enhancing the potency, selectivity and lipophilicity. Here, I developed bivalent Plk1 inhibitors, in which the PBD-binding peptides are conjugated with the known KD-binding inhibitors BI2536 or wortmannin using PEG linkers. These bivalent inhibitors exhibit up to 100-fold enhanced Plk1 affinity relative to the best monovalent PBD-binding ligands, higher selectivity for tested kinases compared to BI2536, and significant cytotoxicity against HeLa cells.
Insights
Researchers developed novel bivalent inhibitors targeting polo-like kinase 1 (Plk1) by linking PBD-binding peptides with kinase domain inhibitors. These compounds show enhanced Plk1 affinity and significant cytotoxicity against cancer cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Polo-like kinase 1 (Plk1) is a Ser/Thr kinase vital for eukaryotic cell cycle regulation.
- Plk1 overexpression correlates with cancer aggressiveness, making it a therapeutic target.
- Plk1's activity is modulated by intramolecular interactions between its kinase domain (KD) and polo-box domain (PBD).
Purpose of the Study:
- To develop cell-active Plk1 inhibitors with enhanced potency and selectivity.
- To overcome the cell membrane permeability limitations of monovalent PBD-binding peptides.
- To explore a bivalent inhibition strategy targeting both Plk1's KD and PBD.
Main Methods:
- Conjugation of PBD-binding peptides with known KD-binding inhibitors (BI2536 or wortmannin) using PEG linkers.
- Development of bivalent Plk1 inhibitors.
- Assessment of Plk1 affinity, kinase selectivity, and cytotoxicity against HeLa cells.
Main Results:
- Bivalent inhibitors demonstrated up to 100-fold increased Plk1 affinity compared to monovalent PBD ligands.
- The developed inhibitors exhibited higher selectivity for tested kinases than BI2536.
- Significant cytotoxicity was observed against HeLa cancer cells.
Conclusions:
- Bivalent inhibition targeting both KD and PBD is a viable strategy for developing potent and selective Plk1 inhibitors.
- These novel bivalent inhibitors show promise as anti-cancer agents due to their enhanced efficacy and cytotoxicity.
- The bivalent approach successfully improved cell permeability and potency, addressing limitations of previous inhibitors.
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