High-Throughput Miniaturized Synthesis of PROTAC-Like Molecules
Ye Tian
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Wenhuaxi Road 44, Jinan, 250012 China
Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Sciences, Shandong University, Wenhuaxi Road 44, Jinan, 250012 China
Search for more papers by this authorMaximilian Seifermann
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorLiana Bauer
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorCharlotte Luchena
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorJanne J. Wiedmann
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorStefan Schmidt
Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), University of Applied Sciences Mannheim, Paul-Wittsack-Straße 10, 68163 Mannheim, Germany
Search for more papers by this authorAlexander Geisel
Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), University of Applied Sciences Mannheim, Paul-Wittsack-Straße 10, 68163 Mannheim, Germany
Search for more papers by this authorSergii Afonin
Institute of Biological Interfaces (IBG-2), Karlsruhe Institute of Technology (KIT), POB 3640, 76021 Karlsruhe, Germany
Search for more papers by this authorJulius Höpfner
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorMarius Brehm
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorXinyong Liu
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Wenhuaxi Road 44, Jinan, 250012 China
Search for more papers by this authorCarsten Hopf
Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), University of Applied Sciences Mannheim, Paul-Wittsack-Straße 10, 68163 Mannheim, Germany
Medical Faculty, Heidelberg University, Im Neuenheimer Feld 280, 69117 Heidelberg, Germany
Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, Heidelberg University, Theodor Kutzer-Ufer 1–3, 68167 Mannheim, Germany
Search for more papers by this authorAnna A. Popova
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorCorresponding Author
Pavel A. Levkin
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
E-mail: [email protected]
Search for more papers by this authorYe Tian
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Wenhuaxi Road 44, Jinan, 250012 China
Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Sciences, Shandong University, Wenhuaxi Road 44, Jinan, 250012 China
Search for more papers by this authorMaximilian Seifermann
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorLiana Bauer
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorCharlotte Luchena
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorJanne J. Wiedmann
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorStefan Schmidt
Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), University of Applied Sciences Mannheim, Paul-Wittsack-Straße 10, 68163 Mannheim, Germany
Search for more papers by this authorAlexander Geisel
Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), University of Applied Sciences Mannheim, Paul-Wittsack-Straße 10, 68163 Mannheim, Germany
Search for more papers by this authorSergii Afonin
Institute of Biological Interfaces (IBG-2), Karlsruhe Institute of Technology (KIT), POB 3640, 76021 Karlsruhe, Germany
Search for more papers by this authorJulius Höpfner
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorMarius Brehm
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorXinyong Liu
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Wenhuaxi Road 44, Jinan, 250012 China
Search for more papers by this authorCarsten Hopf
Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), University of Applied Sciences Mannheim, Paul-Wittsack-Straße 10, 68163 Mannheim, Germany
Medical Faculty, Heidelberg University, Im Neuenheimer Feld 280, 69117 Heidelberg, Germany
Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, Heidelberg University, Theodor Kutzer-Ufer 1–3, 68167 Mannheim, Germany
Search for more papers by this authorAnna A. Popova
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Search for more papers by this authorCorresponding Author
Pavel A. Levkin
Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
E-mail: [email protected]
Search for more papers by this authorAbstract
The development of miniaturized high-throughput in situ screening platforms capable of handling the entire process of drug synthesis to final screening is essential for advancing drug discovery in the future. In this study, an approach based on combinatorial solid-phase synthesis, enabling the efficient synthesis of libraries of proteolysis targeting chimeras (PROTACs) in an array format is presented. This on-chip platform allows direct biological screening without the need for transfer steps. UV-induced release of target molecules into individual droplets facilitates further on-chip experimentation. Utilizing a mitogen-activated protein kinase kinases (MEK1/2) degrader as a template, a series of 132 novel PROTAC-like molecules is synthesized using solid-phase Ugi reaction. These compounds are further characterized using various methods, including matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) imaging, while consuming only a few milligrams of starting materials in total. Furthermore, the feasibility of culturing cancer cells on the modified spots and quantifying the effect of MEK suppression is demonstrated. The miniaturized synthesis platform lays a foundation for high-throughput in situ biological screening of potent PROTACs for potential anticancer activity and offers the potential for accelerating the drug discovery process by integrating miniaturized synthesis and biological steps on the same array.
Conflict of Interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
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| smll202307215-sup-0001-SuppMat.pdf2.3 MB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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