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Published on: June 14, 2021
High-Throughput Miniaturized Synthesis of PROTAC-Like Molecules
Ye Tian1,2,3, Maximilian Seifermann1, Liana Bauer1
1Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.
Researchers developed a miniaturized platform for synthesizing and screening proteolysis targeting chimeras (PROTACs) on-chip. This integrated approach accelerates drug discovery by enabling direct biological testing of novel PROTACs without sample transfer.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Chemical Biology
Background:
- Advancing drug discovery requires efficient synthesis and screening platforms.
- Miniaturized, high-throughput in situ platforms are crucial for future drug development.
Purpose of the Study:
- To present an on-chip platform for combinatorial solid-phase synthesis of proteolysis targeting chimeras (PROTACs).
- To enable direct biological screening of synthesized PROTACs without transfer steps.
- To accelerate the discovery of potential anticancer PROTACs.
Main Methods:
- Combinatorial solid-phase synthesis in an array format.
- On-chip UV-induced release of target molecules for further experimentation.
- Synthesis of 132 novel PROTAC-like molecules using solid-phase Ugi reaction.
- Characterization using MALDI-MS imaging.
- On-chip culturing of cancer cells and quantification of MEK suppression.
Main Results:
- Efficient synthesis of 132 novel PROTAC-like molecules.
- Demonstration of direct on-chip biological screening and MEK suppression.
- Successful characterization with minimal starting material consumption.
- Integration of synthesis and screening on a single platform.
Conclusions:
- The developed platform integrates miniaturized synthesis and biological screening for PROTACs.
- This approach accelerates drug discovery by enabling high-throughput in situ screening.
- It lays the foundation for identifying potent PROTACs with potential anticancer activity.
