In Situ Inhibitor Synthesis and Screening by Fluorescence Polarization: An Efficient Approach for Accelerating Drug...

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Target-directed dynamic combinatorial chemistry (DCC) is valuable for hit identification but complex mixture analysis hinders its use.
• A need exists for simplified, efficient methods in drug discovery for identifying novel inhibitors.

Purpose of the Study:

• To introduce and exemplify the in situ inhibitor synthesis and screening (ISISS) method.
• To demonstrate ISISS's utility in discovering potent inhibitors for therapeutic targets.

Main Methods:

• Developed ISISS, integrating high-throughput bioorthogonal synthesis with fluorescence-based target binding screening.
• Coupled fluorescence polarization screening with acyl-hydrazide and aldehyde reactions.

Main Results:

• Successfully identified a potent and novel acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2).
• The discovered inhibitor showed equivalent in vivo potency to an approved anemia medication.

Conclusions:

• ISISS provides an operationally simple and efficient alternative to traditional DCC for hit identification.
• ISISS facilitates the discovery of novel therapeutic agents, exemplified by the PHD2 inhibitor for anemia treatment.