Article
Oncology
Robin Guo, Michael Offin, A. Rose Brannon, Jason Chang, Andrew Chow, Lukas Delasos, Jeffrey Girshman, Olivia Wilkins, Caroline G. McCarthy, Alex Makhnin, Christina Falcon, Kerry Scott, Yuan Tian, Fabiola Cecchi, Todd Hembrough, Deepu Alex, Ronglai Shen, Ryma Benayed, Bob T. Li, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, Natasha Rekhtman, Paul Paik, Ahmet Zehir, Alexander Drilon
Summary: In MET exon 14-altered lung cancers treated with a MET TKI, the genomic mechanisms of primary resistance remain unknown, while MET expression is correlated with treatment benefit.
CLINICAL CANCER RESEARCH
(2021)
Article
Chemistry, Medicinal
Daowei Huang, Jixia Yang, Qingwei Zhang, Guan Wang, Zixue Zhang, Yue Zhang, Jianqi Li
Summary: In this study, novel N-phenylpyrimidin-2-amine derivatives were developed and many compounds were found to inhibit c-Met kinase, showing high antiproliferative activities in c-Met sensitive tumor cell lines. Compound 34a showed outstanding inhibitory activity and pharmacokinetic properties, making it a potential candidate for c-Met inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Xiaowei Wu, Mengdi Dai, Rongrong Cui, Yulan Wang, Chunpu Li, Xia Peng, Jihui Zhao, Bao Wang, Yang Dai, Dan Feng, Tianbiao Yang, Hualiang Jiang, Meiyu Geng, Jing Ai, Mingyue Zheng, Hong Liu
Summary: The study synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives, with compound 10h showing potent enzymatic activity against FGFR and high anti-tumor efficacy in cancer cells.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Neurosciences
Ruoyu Huang, Yanwei Liu, Kuanyu Wang, Zheng Wang, Chuanbao Zhang, Wei Zhang, Zheng Zhao, Guanzhang Li, Lijie Huang, Yuanhao Chang, Fan Zeng, Tao Jiang, Huimin Hu
Summary: PTPRZ1-MET (ZM) fusion is a critical driver of lower-grade glioma progression and a potential target for MET inhibitors. Early detection using a high-sensitive method of reverse transcriptase PCR is crucial for identifying patients who may benefit from MET inhibitor therapy. The hyperactivation of MET signaling in glioma with ZM fusion may be due to ligand-independent activation enabled by the protein structure modification of the extracellular domain of MET.
CNS NEUROSCIENCE & THERAPEUTICS
(2021)
Article
Pharmacology & Pharmacy
Jin Hui Teh, Ala Amgheib, Ruisi Fu, Chris Barnes, Joel Abrahams, Ali Ashek, Ning Wang, Zixuan Yang, Muneera Mansoorudeen, Nicholas J. J. Long, Eric O. O. Aboagye
Summary: C-Met, a receptor tyrosine kinase overexpressed in various cancer types, has potential as a biomarker for cancer imaging and therapy. This study synthesized and evaluated an [F-18]AlF-labelled analogue, [F-18]AlF-EMP-105, for c-Met imaging using positron emission tomography. In vitro evaluation showed high specificity of [F-18]AlF-EMP-105 for c-Met-expressing cells. PET imaging in mice demonstrated renal clearance of the tracer predominantly as [F-18]fluoride. [F-18]AlF-EMP-105 shows promise as a diagnostic tool for imaging cancer due to its high specificity for c-Met expressing cells.
Article
Biochemistry & Molecular Biology
Yuting Guo, Xia Peng, Yinchun Ji, Yitong Zhang, Jian Ding, Zhengsheng Zhan, Jing Ai, Wenhu Duan
Summary: The synthesized compound 8 was found to have potent antitumor activity by forming two canonical hydrogen bonds and a pi-pi stacking interaction with the ATP binding site of c-Met kinase domain.
MOLECULAR DIVERSITY
(2021)
Article
Oncology
Francesca Bersani, Francesca Picca, Deborah Morena, Luisella Righi, Francesca Napoli, Mariangela Russo, Daniele Oddo, Giuseppe Rospo, Carola Negrino, Barbara Castella, Marco Volante, Angela Listi, Vanessa Zambelli, Federica Benso, Fabrizio Tabbo, Paolo Bironzo, Emanuele Monteleone, Valeria Poli, Filippo Pietrantonio, Federica Di Nicolantonio, Alberto Bardelli, Carola Ponzetto, Silvia Novello, Giorgio V. Scagliotti, Riccardo Taulli
Summary: This study demonstrates that the measurement of circMET levels in the plasma can be used to identify and track patients with high MET activity. It provides a simple, cost-effective, non-invasive approach for implementing patient stratification based on MET expression and monitoring therapy response and clonal evolution during treatment.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2023)
Article
Medicine, Research & Experimental
Dantong Sun, Weizheng Wu, Li Wang, Jialin Qu, Qiman Han, Huiyun Wang, Shanai Song, Ning Liu, Yongjie Wang, Helei Hou
Summary: MET fusions are rare in lung cancer patients, with an occurrence rate of 0.2% to 0.3%. In this study, intragenic MET fusions were found in 52.6% of the included patients. Crizotinib was effective in treating MET fusions, including a new type called EML4-MET fusion. This study sheds light on the rarity and therapeutic potential of MET fusions in lung cancer.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Review
Pharmacology & Pharmacy
Yazan Haddad, Marek Remes, Vojtech Adam, Zbynek Heger
Summary: The study utilized variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. These families shared similar mutational profiles, ligand R-groups facing the C-helix, mutation sites, and DFG domain.
DRUG DISCOVERY TODAY
(2021)
Article
Computer Science, Artificial Intelligence
Xiangcong Zeng, Yuanwen Hu, Zhi Xu, Xiaoyu Wu, Yun Xiong, Shengpeng Liu
Summary: With the progress of times, lung cancer has become increasingly prevalent and has a significant impact on human health. Tumor targeting involves targeting specific abnormal targets in tumor cells or tissues to eliminate tumor cell-specific lesions. This study developed a new c-Met inhibitor and analyzed its application in tumor therapy in combination with a multitarget tyrosine kinase inhibitor. The results showed that the combination of these inhibitors greatly promoted the development of tumor therapy.
Review
Oncology
Chih-Hung Hsu, Yi-Hsiang Huang, Shi-Ming Lin, Chiun Hsu
Summary: AXL and MET play key roles in the progression, treatment resistance, and immunomodulation of HCC. Continued development of drugs that target these receptor tyrosine kinases appears likely to represent a useful strategy to improve outcomes for patients with HCC.
Article
Oncology
Richard Riedel, Jana Fassunke, Hannah L. Tumbrink, Andreas H. Scheel, Carina Heydt, Lena Hieggelke, Matthias Scheffler, Alena Heimsoeth, Lucia Nogova, Sebastian Michels, Jan-Phillip Weber, Rieke N. Fischer, Anna Eisert, Theresa Westphal, Diana Schaufler, Janna Siemanowski, Michaela A. Ihle, Svenja Wagener-Ryczek, Roberta Castiglione, Roberto Pappesch, Jan Rehker, Jessica Juergens, Erich Stoelben, Anne Bunck, Carsten Kobe, Sabine Merkelbach-Bruse, Martin L. Sos, Reinhard Buettner, Juergen Wolf
Summary: This study describes the resistance mechanisms to MET inhibition in MET-dependent non-small cell lung cancer patients, including MET exon 14 skipping mutation, MET amplification, and MET fusion. Analysis of patient samples revealed on-and off-target resistance mechanisms, such as KRAS mutations and HER2 amplification. Switching between different types of kinase inhibitors can lead to repeated responses in some patients.
EUROPEAN JOURNAL OF CANCER
(2023)
Article
Cell Biology
Pinar Ozden Eser, Raymond M. Paranal, Jieun Son, Elena Ivanova, Yanan Kuang, Heidi M. Haikala, Ciric To, Jeffrey J. Okoro, Kshiti H. Dholakia, Jihyun Choi, Yoonji Eum, Atsuko Ogino, Pavlos Missios, Dalia Ercan, Man Xu, Michael J. Poitras, Stephen Wang, Kenneth Ngo, Michael Dills, Masahiko Yanagita, Timothy Lopez, Mika Lin, Jeanelle Tsai, Nicolas Floch, Emily S. Chambers, Jennifer Heng, Rana Anjum, Alison D. Santucci, Kesi Michael, Alwin G. Schuller, Darren Cross, Paul D. Smith, Geoffrey R. Oxnard, David A. Barbie, Lynette M. Sholl, Magda Bahcall, Sangeetha Palakurthi, Prafulla C. Gokhale, Cloud P. Paweletz, George Q. Daley, Pasi A. Janne
Summary: Some EGFR-mutant, MET-amplified lung cancers may develop dependence on MET activation alone, suggesting that these patients could be treated with a single-agent MET TKI instead of the current standard-of-care EGFR and MET inhibitor combination regimens.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Yumiko Tahira, Katsuya Sakai, Hiroki Sato, Ryu Imamura, Kunio Matsumoto
Summary: The researchers found that the residues N127, V140, and K144 at the NK1 dimer interface play important roles in Met activation by HGF. Mutant NK1 proteins with alanine replacements at these residues lost their ability to activate Met, while mutant HGF proteins with the same replacements retained their activity, suggesting a distinction in the structural basis for NK1-dependent Met dimer formation and HGF-dependent Met activation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Rida Rehman, Michael Miller, Sruthi Sankari Krishnamurthy, Jacob Kjell, Lobna Elsayed, Stefanie M. Hauck, Florian Olde Heuvel, Alison Conquest, Akila Chandrasekar, Albert Ludolph, Tobias Boeckers, Medhanie A. Mulaw, Magdalena Goetz, Maria Cristina Morganti-Kossmann, Aya Takeoka, Francesco Roselli
Summary: This study investigates the role of tyrosine-kinase signaling in traumatic brain injury (TBI) using array phosphoproteomics. The findings reveal that Met/HGFR serves as a modulator of early neuroinflammation in TBI and inhibition of Met/HGFR can improve neuronal survival and motor recovery.
Article
Chemistry, Medicinal
Margarita Wucherer-Plietker, Eugen Merkul, Thomas J. J. Mueller, Christina Esdar, Thorsten Knoechel, Timo Heinrich, Hans-Peter Buchstaller, Hartmut Greiner, Dieter Dorsch, Dirk Finsinger, Michel Calderini, David Bruge, Ulrich Graedler
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2016)
Article
Chemistry, Physical
Daria B. Kokh, Marta Amaral, Joerg Bomke, Ulrich Graedler, Djordje Musil, Hans-Peter Buchstaller, Matthias K. Dreyer, Matthias Frech, Maryse Lowinski, Francois Vallee, Marc Bianciotto, Alexey Rak, Rebecca C. Wade
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2018)
Article
Chemistry, Medicinal
Doris A. Schuetz, Lars Richter, Marta Arnaral, Melanie Grandits, Ulrich Graedler, Djordje Musil, Hans-Peter Buchstaller, Hans-Michael Eggenweiler, Matthias Frech, Gerhard F. Ecker
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Chemistry, Medicinal
Ulrich Graedler, Paul Czodrowski, Christos Tsaklakidis, Markus Klein, Daniela Werkmann, Sven Lindemann, Klaus Maskos, Birgitta Leuthner
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2014)
Article
Chemistry, Medicinal
Timo Heinrich, Jeyaprakashnarayanan Seenisamy, Lourdusamy Emmanuvel, Santosh S. Kulkarni, Joerg Bomke, Felix Rohdich, Hartmut Greiner, Christina Esdar, Mireille Krier, Ulrich Graedler, Djordje Musil
JOURNAL OF MEDICINAL CHEMISTRY
(2013)
Article
Chemistry, Medicinal
Ulrich Graedler, Daniel Schwarz, Michael Blaesse, Birgitta Leuthner, Theresa L. Johnson, Frederic Bernard, Xuliang Jiang, Andreas Marx, Marine Gilardone, Hugues Lemoine, Didier Roche, Catherine Jorand-Lebrun
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2019)
Article
Chemistry, Medicinal
Ulrich Graedler, Michael Busch, Birgitta Leuthner, Michael Raba, Lars Burgdorf, Martin Lehmann, Nina Linde, Christina Esdar
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Chemistry, Medicinal
Christina E. M. Schindler, Hannah Baumann, Andreas Blum, Dietrich Boese, Hans-Peter Buchstaller, Lars Burgdorf, Daniel Cappel, Eugene Chekler, Paul Czodrowski, Dieter Dorsch, Merveille K. Eguida, Bruce Follows, Thomas Fuchss, Ulrich Graedler, Jakub Gunera, Theresa Johnson, Catherine Jorand Lebrun, Srinivasa Karra, Markus Klein, Tim Knehans, Lisa Koetzner, Mireille Krier, Matthias Leiendecker, Birgitta Leuthner, Liwei Li, Igor Mochalkin, Djordje Musil, Constantin Neagu, Friedrich Rippmann, Kai Schiemann, Robert Schulz, Thomas Steinbrecher, Eva-Maria Tanzer, Andrea Unzue Lopez, Ariele Viacava Follis, Ansgar Wegener, Daniel Kuhn
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2020)
Article
Biochemistry & Molecular Biology
K. Stakyte, M. Rotheneder, K. Lammens, J. D. Bartho, U. Graedler, T. Fuchss, U. Pehl, A. Alt, E. van de Logt, K. P. Hopfner
Summary: High-resolution cryo-EM structures of human ATM bound to ATP gamma S and two distinct ATM inhibitors provide insights into the mechanism of inhibitor selectivity and offer a framework for structure-based drug design. The mode of action and selectivity of the ATM inhibitors can be explained by structural comparison and provide a framework for structure-based drug design.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2021)
Correction
Chemistry, Medicinal
Ulrich Graedler, Michael Busch, Birgitta Leuthner, Michael Raba, Lars Burgdorf, Martin Lehmann, Nina Linde, Christina Esdar
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Ulrich Graedler, Daniel Schwarz, Ansgar Wegener, Thomas Eichhorn, Tiago M. Bandeiras, Micael C. Freitas, Alfred Lammens, Oleg Ganichkin, Martin Augustin, Stefano Minguzzi, Frank Becker, Jorg Bomke
Summary: In this study, the researchers investigated the impact of A-loop conformation on the binding of the MET inhibitor tepotinib. They used protein crystallography, biophysical methods, and mass spectrometry to study different recombinant MET kinase domain (KD) protein variants. The results showed that mutations, phosphorylation status, and pi-stacking interactions can affect the residence time of tepotinib. This study provides valuable insights into the structural determinants of the MET A-loop that influence the binding of tepotinib.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Analytical
Ana C. F. Paiva, Ana R. Lemos, Philipp Busse, Madalena T. Martins, Diana O. Silva, Micael C. Freitas, Sandra P. Santos, Filipe Freire, Evelyne J. Barrey, Xavier Manival, Lisa Koetzner, Timo Heinrich, Ansgar Wegener, Ulrich Graedler, Tiago M. Bandeiras, Daniel Schwarz, Pedro M. F. Sousa
Summary: Modern drug discovery relies on combinatorial screening campaigns to find drug molecules targeting specific disease-associated proteins. The Extract2Chip method described in this study allows for the direct immobilization of site-specific biotinylated proteins from cellular extracts onto avidin-coated sensor chips, enabling the characterization of molecular interactions via surface plasmon resonance. This method provides a potential solution for drug discovery campaigns that have been hindered by the lack of suitable and sufficient protein supply.
Meeting Abstract
Oncology
Nina Linde, Andreas Blum, Dieter Dorsch, Ulrich Graedler, Michael Busch, Nina Glaser, Carl Petersson, Aaron Ruff, Eva Sherbetjian, Christina Esdar
Meeting Abstract
Oncology
Thomas Fuchss, Ulrich Graedler, Kai Schiemann, Daniel Kuhn, Holger Kubas, Heike Dahmen, Astrid Zimmermann, Frank Zenke, Andree Blaukat
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)