Mike Bührmann

TU Dortmund University

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Daniel Rauh

TU Dortmund University

Julia Hardick

TU Dortmund University

Heike K. Wentsch

University of Tübingen

Matthias Müller

TU Dortmund University

Rogier C. Buijsman

Center for Translational Molecular Medicine

Svenja Mayer‐Wrangowski

Boehringer Ingelheim (Germany)

Nicole Willemsen‐Seegers

Center for Translational Molecular Medicine

Niklas M. Walter

Karlsruhe Institute of Technology

Stefan Laufer

University of Tübingen

Guido J.R. Zaman

Center for Translational Molecular Medicine

Cooperative Institutions

TU Dortmund University

University of Cologne

University Hospital Cologne

University of Tübingen

Weizmann Institute of Science

Max Planck Society

Max Planck Institute for Metabolism Research

German Cancer Research Center

Heinrich Heine University Düsseldorf

Integrated Oncology (United States)

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Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38α MAPK

PLoS ONE (2017)

Mike Bührmann Bianca Wiedemann Matthias Müller Julia Hardick Maria Ecke

In protein kinase research, identifying and addressing small molecule binding sites other than the highly conserved ATP-pocket are of intense interest because this line of investigation extends our understanding of kinase function beyond the catalytic phosphotransfer. Such alternative binding sites may be involved in altering the activation state through subtle conformational changes, control cellular enzyme localization, or in mediating and disrupting protein-protein interactions. Small organic molecules that target these less conserved regions might serve as tools for chemical biology research and to probe alternative strategies in targeting protein kinases in disease settings. Here, we present the structure-based design and synthesis of a focused library of 2-arylquinazoline derivatives to target the lipophilic C-terminal binding pocket in p38α MAPK, for which a clear biological function has yet to be identified. The interactions of the ligands with p38α MAPK was analyzed by SPR measurements and validated by protein X-ray crystallography.

Chemical Biology

10.1371/journal.pone.0184627

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Citations (11)

Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors

Science Translational Medicine (2017)

Dennis Plenker M Riedel Johannes Brägelmann Marcel A. Dammert Rakhee Chauhan

Oncogenic fusion events have been identified in a broad range of tumors. Among them,

Proto-Oncogene Proteins c-ret

10.1126/scitranslmed.aah6144

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Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer

Dennis Plenker M Riedel Johannes Brägelmann Dammert Rakhee Chauhan

Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. Here, we provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors such as AD80 or ponatinib that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells we identify the CCDC6-RETI788N mutation and drug-induced MAPK pathway reactivation as possible mechanisms, by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.

Druggability

Ponatinib

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Kovalente Liganden zur Adressierung einer lipophilen Bindetasche in der MAPK p38α

Angewandte Chemie (2017)

Mike Bührmann Julia Hardick Jörn Weisner Lena Quambusch Daniel Rauh

Abstract Ein chemisch‐genetischer Ansatz zur kovalenten Adressierung einer einzigartigen lipophilen Bindetasche (LP) in der Mitogen‐aktivierten Proteinkinase p38α, deren physiologische Funktion bis heute nicht völlig verstanden ist, wird vorgestellt. Basierend auf einer Reihe von Kokristallstrukturen wurde eine fokussierte Substanzbibliothek von 2‐Arylchinazolinen entwickelt, die mit Elektrophilen versehen wurden, um p38α‐Mutanten mit artifiziell eingeführten Cysteinen zu generieren. Aufeinander abgestimmte Protein‐Liganden‐Paare wurden über MS‐Analysen identifiziert und mittels MS/MS‐basierten sowie kristallographischen Studien validiert. Einige der kovalenten Liganden, die aus diesem Ansatz hervorgingen, zeigten eine hervorragende Selektivität für jeweils eine einzelne p38α‐Mutante und können zukünftig als Sondenmoleküle zur Aufklärung der LP‐Funktion im Rahmen pharmakologischer Perturbationsexperimente in zellulären Systemen Anwendung finden.

10.1002/ange.201706345

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Functional and structural characterization of a novel class of MAP-kinase inhibitors

Free Radical Biology and Medicine (2017)

Desirée Bartolini Mike Bührmann Maria Letizia Barreca Giuseppe Manfroni Violetta Cecchetti

10.1016/j.freeradbiomed.2017.04.224

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Optimized Target Residence Time: Type I Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R‐Spine

Angewandte Chemie International Edition (2017)

Heike K. Wentsch Niklas M. Walter Mike Bührmann Svenja Mayer‐Wrangowski Daniel Rauh

Abstract Skepinone‐L was recently reported to be a p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, this class of compounds still act as fully ATP‐competitive Type I binders which, furthermore, suffer from short residence times at the enzyme. We herein describe a further development with the first Type I binders for p38α MAP kinase. Type I inhibitors interfere with the R‐spine, inducing a glycine flip and occupying both hydrophobic regions I and II. This design approach leads to prolonged target residence time, binding to both the active and inactive states of the kinase, excellent selectivity, excellent potency on the enzyme level, and low nanomolar activity in a human whole blood assay. This promising binding mode is proven by X‐ray crystallography.

10.1002/anie.201701185

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Optimization of Covalent MKK7 Inhibitors via Crude Nanomole-Scale Libraries

Journal of Medicinal Chemistry (2022)

Paul Gehrtz Shir Marom Mike Bührmann Julia Hardick Silke Kleinbölting

High-throughput nanomole-scale synthesis allows for late-stage functionalization (LSF) of compounds in an efficient and economical manner. Here, we demonstrated that copper-catalyzed azide-alkyne cycloaddition could be used for the LSF of covalent kinase inhibitors at the nanoscale, enabling the synthesis of hundreds of compounds that did not require purification for biological assay screening, thus reducing experimental time drastically. We generated crude libraries of inhibitors for the kinase MKK7, derived from two different parental precursors, and analyzed them via the high-throughput In-Cell Western assay. Select inhibitors were resynthesized, validated via conventional biological and biochemical methods such as western blots and liquid chromatography-mass spectrometry (LC-MS) labeling, and successfully co-crystallized. Two of these compounds showed over 20-fold increased inhibitory activity compared to the parental compound. This study demonstrates that high-throughput LSF of covalent inhibitors at the nanomole-scale level can be an auspicious approach in improving the properties of lead chemical matter.

Alkyne

High-Throughput Screening

10.1021/acs.jmedchem.1c02206

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Optimierte Bindungsdauer am Zielenzym: Typ‐I‐Inhibitoren der p38α‐MAP‐Kinase mit verbesserter Bindungskinetik durch direkte Interaktion mit der R‐Spine

Angewandte Chemie (2017)

Heike K. Wentsch Niklas M. Walter Mike Bührmann Svenja Mayer‐Wrangowski Daniel Rauh

Abstract Vor kurzem wurde mit Skepinone‐L ein p38α‐MAP‐Kinase‐Inhibitor mit hoher Potenz und ausgezeichneter Selektivität in vitro und in vivo beschrieben. Der Bindemodus dieser Substanzklasse entspricht allerdings dem eines ATP‐kompetitiven Typ‐I‐Inhibitors mit kurzer Verweildauer am Enzym. Nun wurde Skepinone‐L zu den ersten Typ‐I ‐Inhibitoren der p38α‐MAP‐Kinase weiterentwickelt. Typ‐I ‐Inhibitoren stören den Aufbau der R‐Spine, induzieren einen Glycin‐Flip und besetzen beide hydrophobe Bindetaschen, die hydrophobe Region I und II. Dieses Konzept führte zu Inhibitoren mit verlängerter Verweildauer am Enzym, die sowohl die aktive als auch die inaktive Kinase binden. Des Weiteren kennzeichnet sie eine herausragende Selektivität gegenüber anderen Kinasen sowie eine ausgezeichnete Wirkung am isolierten Enzym. Darüber hinaus reicht ihre Hemmwirkung in einem humanen Vollblut‐Assay bis tief in den nanomolaren Bereich. Dieser neue Bindemodus konnte röntgenkristallographisch belegt werden.

10.1002/ange.201701185

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CCDC 1517339: Experimental Crystal Structure Determination

The Cambridge Structural Database (2017)

Jakob Halekotte Lydia Witt Chiara Ianes Marcus Krüger Mike Bührmann

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/ccdc.csd.cc1mxxfw

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Co-crystal structure determination and cellular evaluation of 1,4-dihydropyrazolo[4,3-c] [1,2] benzothiazine 5,5-dioxide p38α MAPK inhibitors

Biochemical and Biophysical Research Communications (2019)

Desirée Bartolini Mike Bührmann Maria Letizia Barreca Giuseppe Manfroni Violetta Cecchetti

10.1016/j.bbrc.2019.02.063

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Citations (8)