Design, synthesis, and functional evaluation of triazine-based bivalent agents that simultaneously target the active
Yosei Nagaoka1, Prakash Parvatkar2, Go Hirai3
1Academic Assembly, Institute of Agriculture, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano 399-04598, Japan.
Abstract:
Cdc25B phosphatase catalyzes the dephosphorylation and activation of cyclin-dependent kinases 2 (CDK2/CycA) and their overexpression has been reported in cancers. Although Cdc25B has received much attention as a drug target, its flat and featureless surface makes it challenging to develop new agents targeting this protein. In this study, we investigated the rational design of a series of bivalent triazine-based derivatives with the aim of simultaneously targeting the active site and the remote hotspot critical for the interaction with CDK2/CycA. Compounds 1e and 10, containing aromatic residues, were shown to inhibit Cdc25B activity selectively over Cdc25A at low micromolar concentration.
Insights
Researchers designed novel bivalent triazine compounds to target the Cdc25B phosphatase, an enzyme overexpressed in cancers. Compounds 1e and 10 selectively inhibited Cdc25B at low micromolar concentrations, offering a promising new avenue for cancer drug development.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Cdc25B phosphatase is crucial for activating cyclin-dependent kinases (CDK2/CycA).
- Overexpression of Cdc25B is linked to various cancers.
- The protein's flat surface presents challenges for drug development.
Purpose of the Study:
- To rationally design novel bivalent triazine derivatives targeting Cdc25B.
- To simultaneously inhibit the active site and a remote hotspot of Cdc25B.
- To develop selective inhibitors for Cdc25B over Cdc25A.
Main Methods:
- Design and synthesis of bivalent triazine-based compounds.
- Evaluation of inhibitory activity against Cdc25B.
- Assessment of selectivity against Cdc25A phosphatase.
Main Results:
- Several bivalent triazine derivatives were synthesized.
- Compounds 1e and 10 demonstrated potent inhibition of Cdc25B.
- These compounds exhibited selectivity for Cdc25B over Cdc25A at low micromolar concentrations.
Conclusions:
- Bivalent triazine derivatives can effectively target Cdc25B.
- Compounds 1e and 10 represent promising lead compounds for cancer therapy.
- The dual-targeting strategy overcomes challenges associated with Cdc25B's structure.
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