Article
Chemistry, Medicinal
Ping Sun, Jing Wang, Khadija S. Khan, Weiqin Yang, Billy Wai-Lung Ng, Nikita Ilment, Matthes Zessin, Emre F. Buelbuel, Dina Robaa, Frank Erdmann, Matthias Schmidt, Christophe Romier, Mike Schutkowski, Alfred Sze-Lok Cheng, Wolfgang Sippl
Summary: This study identifies a HDAC8 inhibitor with T cell modulatory properties and demonstrates its potential in reducing hepatocellular carcinoma tumorigenicity.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Qing Tang, Alex M. Aronov, David D. Deininger, Simon Giroux, David J. Lauffer, Pan Li, Jianglin Liang, Kira McGinty, Steven Ronkin, Rebecca Swett, Nathan Waal, Diane Boucher, Pamella J. Ford, Cameron S. Moody
Summary: In this study, a novel series of highly potent and selective triazolothiadiazole c-Met inhibitors were developed, with compound 23 showing excellent kinase selectivity and dose-dependent antitumor efficacy in a SNU-5 gastric cancer xenograft model.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Chaofan Wang, Jie Li, Lingzhi Qu, Xia Tang, Xiaojuan Song, Fang Yang, Xiaojuan Chen, Qianmeng Lin, Weibin Lin, Yang Zhou, ZhengChao Tu, Yongheng Chen, Zhang Zhang, Xiaoyun Lu
Summary: MET alterations are crucial in NSCLC and gastric cancers. We designed and optimized a series of new c-Met inhibitors using molecular hybridization and macrocyclization strategy, among which D6808 exhibited potent inhibitory activity, extraordinary target specificity, and promise for further anticancer drug development.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Mark E. Layton, Jeffrey C. Kern, Timothy J. Hartingh, William D. Shipe, Izzat Raheem, Monika Kandebo, Robert P. Hayes, Sarah Huszar, Donnie Eddins, Bennett Ma, Joy Fuerst, Gordon K. Wollenberg, Jing Li, Jeff Fritzen, Georgia B. McGaughey, Jason M. Uslaner, Sean M. Smith, Paul J. Coleman, Christopher D. Cox
Summary: PDE10A is an important regulator of striatal signaling. Inhibition of PDE10A may offer a new treatment option for schizophrenia. This study describes the discovery of an isomeric pyrimidine series that led to the development of compound 18 (MK-8189), which is currently in Phase 2b clinical development for schizophrenia.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Ruifang Jia, Jian Zhang, Chiara Bertagnin, Srinivasulu Cherukupalli, Wei Ai, Xiao Ding, Zhuo Li, Jiwei Zhang, Han Ju, Xiuli Ma, Arianna Loregian, Bing Huang, Peng Zhan, Xinyong Liu
Summary: The structural modifications at the 150-cavity of influenza virus neuraminidases can result in more potent oseltamivir derivatives, with compound 5c showing the most promising activity. In vitro and in vivo studies demonstrated low cytotoxicity and no acute toxicity of 5c, indicating its potential as a drug candidate.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Xue Zhong, Huiwen Deng, Min Long, Honglu Yin, Qiu Zhong, Shilong Zheng, Tao Gong, Ling He, Guangdi Wang, Qiu Sun
Summary: Berberine was discovered as a potent p300/CBP HAT inhibitor and showed inhibition of tumor growth. Novel analog 5d, derived from berberine, demonstrated high selectivity towards p300/CBP HAT and effectively suppressed tumor growth in animal models. Furthermore, liposomes-encapsulated 5d showed increased inhibition of tumor growth with good absorption properties in vivo.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Jinyun Dong, Guang Huang, Qing Cui, Qingqing Meng, Shaoshun Li, Jiahua Cui
Summary: A series of 6,7,10-trimethoxy-alpha-naphthoflavone derivatives with variations in B ring were synthesized and screened, leading to the identification of fluorine-containing compound 15i as the most potent and selective CYP1B1 inhibitor. Amino-substituted derivative 13h showed potent inhibitory effect on CYP1B1 and increased water solubility compared to the lead molecule ANF.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Liqiang Fu, Jing Zhang, Bin Shen, Linglong Kong, Yingtao Liu, Wangyang Tu, Wenqian Wang, Xin Cai, Xiaotao Wang, Na Cheng, Mingxuan Xia, Tianyuan Zhou, Qian Liu, Yanping Xu, Jennifer Yang, Paul Gavine, Ulrike Philippar, Ricardo Attar, James P. Edwards, Jennifer D. Venable, Xuedong Dai
Summary: The study discusses the potent anti-proliferative effects of IRAK1 degraders on ABC DLBCL cells with MyD88 mutation, as well as their inhibitory effects on IRAK1 downstream signaling pathways, indicating the potential of these IRAK1 degraders for treating cancers dependent on IRAK1 scaffolding function.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Bernard Barlaam, Chris De Savi, Allan Dishington, Lisa Drew, Andrew D. Ferguson, Douglas Ferguson, Chungang Gu, Sudhir Hande, Lorraine Hassall, Janet Hawkins, Alexander W. Hird, Jane Holmes, Michelle L. Lamb, Andrew S. Lister, Thomas M. McGuire, Jane E. Moore, Nichole O'Connell, Anil Patel, Kurt G. Pike, Ujjal Sarkar, Wenlin Shao, Darren Stead, Jeffrey G. Varnes, Melissa M. Vasbinder, Lei Wang, Liangwei Wu, Lin Xue, Bin Yang, Tieguang Yao
Summary: The discovery of azaindoles 38 and 39 as highly potent and selective CDK9 inhibitors suitable for intravenous administration, with the potential to achieve transient inhibition of CDK9 in vivo, represents a significant advancement in the development of treatment for hematological malignancies. Further optimization focusing on physicochemical and pharmacokinetic properties played a crucial role in the development of these compounds.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Yunjiang Zhou, Yunting Zou, Mei Yang, Shuang Mei, Xiaohao Liu, Huiyun Han, Chang-Dong Zhang, Miao-Miao Niu
Summary: This study demonstrates that a cyclic D-peptide NKTP-3, targeting both NRP1 and KRAS(G12D), could be a potential chemotherapeutic agent for KRAS(G12D)-driven lung cancer treatment.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Medicinal
Hector de Lucio, Javier Garcia-Marin, Patricia Sanchez-Alonso, Juan Carlos Garcia-Soriano, Miguel Angel Toro, Juan J. Vaquero, Federico Gago, Ramon Alajarin, Antonio Jimenez-Ruiz
Summary: In this study, fifteen pyridazino-pyrrolo-quinoxalinium salts were synthesized and tested for their antiprotozoal activity against Leishmania infantum amastigotes. Eleven of them showed potent leishmanicidal activity with low toxicity against human cells. Compounds 3b and 3f were identified as potent inhibitors of the oxidoreductase activity of the essential enzyme trypanothione disulfide reductase (TryR).
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Umm-E-Farwa, Saeed Ullah, Maria Aqeel Khan, Humaira Zafar, Atia-tul-Wahab, Munisaa Younus, M. Iqbal Choudhary, Fatima Z. Basha
Summary: The study designed new molecules for treating diabetes, with most compounds showing potent inhibitory activity against alpha-glucosidase. These active isoxazoles interacted with critical amino acid residues of alpha-glucosidase, potentially becoming promising drug candidates for diabetes treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Jianzhang Yang, Yu Chang, Jean Ching-Yi Tien, Zhen Wang, Yang Zhou, Pujuan Zhang, Weixue Huang, Josh Vo, Ingrid J. Apel, Cynthia Wang, Victoria Zhixuan Zeng, Yunhui Cheng, George Xiaoju Wang, Arul M. Chinnaiyan, Ke Ding
Summary: In this study, highly potent and selective dual CDK12/13 degraders were discovered using the PROTAC technology. The optimal compound 7f effectively degraded CDK12 and CDK13, and inhibited the proliferation of TNBC cell lines.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Pedro Besada, Dolores Vina, Tamara Costas, Maria Carmen Costas-Lago, Noemi Vila, Iria Torres-Teran, Mattia Sturlese, Stefano Moro, Carmen Teran
Summary: A novel class of potential MAO-B inhibitors were designed and synthesized by combining pyridazinone moiety and dithiocarbamate framework, showing reversible and selective inhibition of hMAO-B in vitro with low cellular toxicity. Among the hybrids, compounds with specific structural fragments displayed the most attractive activity. Molecular modeling studies helped analyze the binding mode, structure-activity relationships, and drug-like properties of the compounds.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Mohamed H. Elsherbeny, Jushin Kim, Noha A. Gouda, Lizaveta Gotina, Jungsook Cho, Ae Nim Pae, Kyeong Lee, Ki Duk Park, Ahmed Elkamhawy, Eun Joo Roh
Summary: A series of novel indole-based small molecules were synthesized as MAO-B inhibitors, with compounds 7b, 8a, 8b, and 8e showing excellent inhibitory effects and selectivity indices, potentially counteracting oxidative stress and displaying safe neurotoxicity profiles in PC12 cells.
Article
Chemistry, Medicinal
Dieter Dorsch, Oliver Schadt, Frank Stieber, Michael Meyring, Ulrich Graedler, Friedhelm Bladt, Manja Friese-Hamim, Christine Knuehl, Ulrich Pehl, Andree Blaukat
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2015)
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