MTX conjugates for identification of new targets using MASPIT
The number of therapeutic targets that the modern pharmacopoeia acts on is surprisingly small (ca. 500) and only a small fraction of the recently approved drugs interferes with new target families.
This project aims to explore MASPIT, a 3-hybrid variant developed in the Cytokine Receptor Laboratory (CRL), for the identification of novel intracellular therapeutic targets.
In MASPIT a dihydrofolate reductase fusion protein forms a high affinity binding site for the methotrexate (MTX) part of a MTX–“bait” conjugate, allowing to present a “bait” compound to the intracellular environment. A “bait”–“prey” interaction activates the JAK2-STAT3 signalization and can be easily detected via a reporter protein (e.g., luciferase), whose expression is controlled by a STAT3-responsive promoter.
Our role in this project involves the synthesis of versatile MTX building blocks which will be used for the construction of MTX–“bait” conjugates of a series of therapeutically interesting small molecules.
Identification of new intracellular targets may feed new target-based drug discovery projects.
Researcher: Dr. Martijn Risseeuw
Collaborators: Prof. Jan Tavernier, Dr. Sam Lievens (Cytokine Receptor Laboratory, UGent)