Marina Keul
Technical University of Dortmund
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Publication
Featured researches published by Marina Keul.
Journal of Medicinal Chemistry | 2015
Julian Engel; André Richters; Matthäus Getlik; Stefano Tomassi; Marina Keul; Termathe M; Jonas Lategahn; Christian F. W. Becker; Svenja Mayer-Wrangowski; Christian Grütter; Uhlenbrock N; Krüll J; Schaumann N; Eppmann S; Patrick Kibies; Franziska Hoffgaard; Jochen Heil; Sascha Menninger; Sandra Ortiz-Cuaran; Johannes M. Heuckmann; Tinnefeld; René P. Zahedi; Martin L. Sos; Carsten Schultz-Fademrecht; Roman K. Thomas; Stefan M. Kast; Daniel Rauh
Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.
Angewandte Chemie | 2016
Julian Engel; Christian Becker; Jonas Lategahn; Marina Keul; Julia Ketzer; Thomas Mühlenberg; Laxmikanth Kollipara; Carsten Schultz-Fademrecht; René P. Zahedi; Sebastian Bauer; Daniel Rauh
Targeting acquired drug resistance represents the major challenge in the treatment of EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we describe the structure-based design, synthesis, and biological evaluation of a novel class of covalent EGFR inhibitors that exhibit excellent inhibition of EGFR-mutant drug-resistant cells. Protein X-ray crystallography combined with detailed kinetic studies led to a deeper understanding of the mode of inhibition of EGFR-T790M and provided insight into the key principles for effective inhibition of the recently discovered tertiary mutation at EGFR-C797S.
Journal of Medicinal Chemistry | 2017
Stefano Tomassi; Jonas Lategahn; Julian Engel; Marina Keul; Hannah L. Tumbrink; Julia Ketzer; Thomas Mühlenberg; Matthias Baumann; Carsten Schultz-Fademrecht; Sebastian Bauer; Daniel Rauh
The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks a drastic change in the treatment of non-small cell lung cancer (NSCLC). The recurrent emergence of resistance to these targeted drugs requires the development of novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report the optimization process for a hit compound that has emerged from a phenotypic screen resulting in indazole-based compounds. These inhibitors are conformationally less flexible, target gatekeeper mutated drug-resistant EGFR-L858R/T790M, and covalently alkylate Cys797. Western blot analysis, as well as characterization of the binding kinetics and kinase selectivity profiling, substantiates our approach of targeting drug-resistant EGFR-L858R/T790M with inhibitors incorporating the indazole as hinge binder.
Journal of Medicinal Chemistry | 2017
Marcel Günther; Jonas Lategahn; Michael Juchum; Eva Döring; Marina Keul; Julian Engel; Hannah L. Tumbrink; Daniel Rauh; Stefan Laufer
Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity. Guided by molecular modeling, we synthesized and studied the structure-activity relationship of 40 compounds against clinically relevant EGFR mutants. We successfully improved the cellular EGFR inhibition down to the low nanomolar range with covalently binding inhibitors against a gefitinib resistant T790M mutant cell line. We identified additional noncovalent interactions, which allowed us to develop metabolically stable inhibitors with high activities against the osimertinib resistant L858R/T790M/C797S mutant.
Science Translational Medicine | 2017
Dennis Plenker; Maximilian Riedel; Johannes Brägelmann; Marcel A. Dammert; Rakhee Chauhan; Phillip P. Knowles; Carina Lorenz; Marina Keul; Mike Bührmann; Oliver Pagel; Verena Tischler; Andreas H. Scheel; Daniel Schütte; Yanrui Song; Justina Stark; Florian Mrugalla; Yannic Alber; André Richters; Julian Engel; Frauke Leenders; Johannes M. Heuckmann; Jürgen Wolf; Joachim Diebold; Georg Pall; Martin Peifer; Maarten Aerts; Kris Gevaert; René P. Zahedi; Reinhard Buettner; Kevan M. Shokat
An examination of the activity profiles of RET inhibitors suggests potential treatment for RET-rearranged cancers. RET-ting out lung tumors Gene fusions and rearrangements serve as oncogenic drivers in a number of tumor types, and some of these can be targeted with existing drugs. RET rearrangements have been identified as drivers in some lung adenocarcinomas, but previous attempts to target RET have not been successful. Plenker et al. determined why the drugs previously proposed for inhibiting RET were not sufficiently potent and showed that successful inhibition of RET requires the ability to bind RET in its catalytically inactive conformation, known as the “DFG-out conformation,” thus locking it in an inactive state. The authors also identified drugs that bind RET in the desired conformation and demonstrated their efficacy in patient-derived xenograft models. 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. 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 mitogen-activated protein kinase 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.
Angewandte Chemie | 2018
Jonas Lategahn; Marina Keul; Daniel Rauh
The treatment of non-small cell lung cancer (NSCLC) is currently experiencing a revolution. Over the last decade, the knowledge gained about the biochemical features of biomarkers and their predictive abilities has led to the development of targeted small-molecule inhibitors that present an alternative to harsh chemotherapy. The use of these new therapies has improved the quality of life and increased the survival of patients. The occurrence of inevitable drug resistance requires the constant development of precision medicine. The detailed understanding of the target biology and the search for innovative chemical approaches has encouraged investigations in this field. Herein, we review selected aspects of the molecular targets and present an overview of current topics and challenges in the rational development of small molecules to target NSCLC.
Journal of Medicinal Chemistry | 2017
Julian Engel; Steven J. Smith; Jonas Lategahn; Hannah L. Tumbrink; Lisa Goebel; Christian F. W. Becker; Elisabeth Hennes; Marina Keul; Anke Unger; Heiko Müller; Matthias Baumann; Carsten Schultz-Fademrecht; Georgia Günther; Jan G. Hengstler; Daniel Rauh
Reversible epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance. These inhibitors exhibited strong inhibitory effects toward EGFR kinase activity and excellent inhibition of cell growth in the drug-resistant cell line H1975, without significantly affecting EGFR wild-type cell lines. Additionally, we present the in vitro ADME/DMPK parameters for a subset of the inhibitors as well as in vivo pharmacokinetics in mice for a candidate with promising activity profile.
ChemMedChem | 2018
Patrik Wolle; Jörn Weisner; Marina Keul; Ina Landel; Jonas Lategahn; Daniel Rauh
The identification of compounds for dissecting biological functions and the development of novel drug molecules are central tasks that often require screening campaigns. However, the required architecture is cost‐ and time‐intensive. Herein we describe the devices and technologies that comprise a Robotics‐Assisted Screening Platform for Efficient Ligand Discovery (RASPELD), which we set up in an academic laboratory. RASPELD provides semi‐automated high‐end screening, and it can be maintained by graduate students. We demonstrate its successful application in biochemical and cellular screens for the identification and validation of bioactive chemical entities as candidate cancer‐relevant inhibitors. Specifically, we examined the interaction between a transcription factor, Nrf2, and its key regulator, Keap1. We also examined drug‐resistant mutants of the epidermal growth factor receptor (EGFR). Screening campaigns with more than 30 000 compounds were performed in a reasonable period of time. We identified the molecule RSL6586 as a starting point for hit optimization, which is currently ongoing.
Journal of Medicinal Chemistry | 2017
Helena Kaitsiotou; Marina Keul; Julia Hardick; Thomas Mühlenberg; Julia Ketzer; Christiane Ehrt; Jasmin Krüll; Federico Medda; Oliver Koch; Fabrizio Giordanetto; Sebastian Bauer; Daniel Rauh
In modern cancer therapy, the use of small organic molecules against receptor tyrosine kinases (RTKs) has been shown to be a valuable strategy. The association of cancer cells with dysregulated signaling pathways linked to RTKs represents a key element in targeted cancer therapies. The tyrosine kinase mast/stem cell growth factor receptor KIT is an example of a clinically relevant RTK. KIT is targeted for cancer therapy in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). However, acquired resistance mutations within the catalytic domain decrease the efficacy of this strategy and are the most common cause of failed therapy. Here, we present the structure-based design and synthesis of novel type II kinase inhibitors to overcome these mutations in KIT. Biochemical and cellular studies revealed promising molecules for the inhibition of mutated KIT.
ACS Omega | 2017
Steven J. Smith; Marina Keul; Julian Engel; Debjit Basu; Simone Eppmann; Daniel Rauh
Within the spectrum of kinase inhibitors, covalent-reversible inhibitors (CRIs) provide a valuable alternative approach to classical covalent inhibitors. This special class of inhibitors can be optimized for an extended drug-target residence time. For CRIs, it was shown that the fast addition of thiols to electron-deficient olefins leads to a covalent bond that can break reversibly under proteolytic conditions. Research groups are just beginning to include CRIs in their arsenal of compound classes, and, with that, the understanding of this interesting set of chemical warheads is growing. However, systems to assess both characteristics of the covalent-reversible bond in a simple experimental setting are sparse. Here, we have developed an efficient methodology to characterize the covalent and reversible properties of CRIs and to investigate their potential in targeting clinically relevant variants of the receptor tyrosine kinase EGFR.