Article
Chemistry, Medicinal
Francesca Quartieri, Marcella Nesi, Nilla R. Avanzi, Daniela Borghi, Elena Casale, Emiliana Corti, Ulisse Cucchi, Daniele Donati, Marina Fasolini, Eduard R. Felder, Arturo Galvani, Maria L. Giorgini, Antonio Lomolino, Maria Menichincheri, Christian Orrenius, Claudia Perrera, Stefania Re Depaolini, Federico Riccardi-Sirtori, Enea Salsi, Antonella Isacchi, Paola Gnocchi
Summary: This article describes the identification of unprecedented ATP-competitive ChoK alpha inhibitors starting from an initial hit NMS-P830. The structure-based medicinal chemistry program resulted in the discovery of selective compounds with good biochemical activity, solubility, and metabolic stability, suitable for further optimization. The ChoK alpha inhibitors disclosed in this study are the first to demonstrate the potential for inhibiting ChoK alpha with ATP-competitive compounds.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Sandra Roehm, Benedict-Tilman Berger, Martin Schroeder, Deep Chatterjee, Sebastian Mathea, Andreas C. Joerger, Daniel M. Pinkas, Joshua C. Bufton, Amelie Tjaden, Lohitesh Kovooru, Mark Kudolo, Christian Pohl, Alex N. Bullock, Susanne Mueller, Stefan Laufer, Stefan Knapp
Summary: In this study, a potent and cell-active dual DDR/p38 chemical probe was developed, along with a structurally related negative control, for studying DDR kinase signaling. The structure-guided design approach provided insights into the folding process of p38 and how non-conserved amino acids modulate inhibitor selectivity. The developed DDR/p38 probe is a valuable tool for investigating the role of DDR kinase in normal physiology and disease development.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Mengxia Sun, Chi Zhang, Dexin Sui, Canchai Yang, Dohun Pyeon, Xuefei Huang, Jian Hu
Summary: Phosphatidylinositol phosphate kinases (PIPKs) are enzymes that produce lipid signaling molecules and have become attractive drug targets for various diseases. Researchers have designed and synthesized D-galactosyl lysophospholipids, which can selectively target phosphatidylinositol 4-phosphate 5-kinase. This study also discovered a human PIKfyve inhibitor that enhances the inhibition of Apilimod, an ATP-competitive PIKfyve inhibitor, in clinical trials for SARS-CoV-2 infection and amyotrophic lateral sclerosis. These findings demonstrate the potential of D-galactose-based phosphoinositide mimetics as artificial substrates and inhibitors of PIPKs.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Review
Chemistry, Medicinal
Shivani Patel, Vivek K. Vyas, Manmohan Sharma, Manjunath Ghate
Summary: Casein kinase 2 (CK2) is a widely present serine-threonine kinase with diverse functions. It has emerged as a potential drug target for cancer and related disorders. This review provides a comprehensive overview of CK2 protein, its binding pocket, current clinical trial candidates, and structure-guided drug design approaches for CK2 inhibitors. The authors also discuss the importance of CK2 co-crystal structures in facilitating inhibitor discovery.
FUTURE MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Huabin Hu, Oliver Laufkoetter, Filip Miljkovic, Juergen Bajorath
Summary: Allosteric and ATP-competitive kinase inhibitors act through distinct mechanisms and have different kinase selectivity levels. Despite this, structural analysis revealed that many of these inhibitors contain similar substructures, with some allosteric inhibitors sharing core structures with ATP site-directed inhibitors. Small chemical modifications of common cores can lead to the development of either allosteric or competitive inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Christopher M. Brennan, Abby S. Hill, Michael St Andre, Xianfeng Li, Vijaya Madeti, Susanne Breitkopf, Seth Garren, Liang Xue, Tamara Gilbert, Angela Hadjipanayis, Mara Monetti, Charles P. Emerson Jr, Robert Moccia, Jane Owens, Nicolas Christoforou
Summary: This study investigated the kinetics of DUX4-induced stresses and found that the JNK and p38 MAP kinase pathways are activated in DUX4-mediated FSHD, providing further insights into potential therapeutic targets.
DISEASE MODELS & MECHANISMS
(2022)
Article
Chemistry, Medicinal
Esther Carrasco, Patricia Gomez-Gutierrez, Pedro M. Campos, Miguel Vega, Angel Messeguer, Juan J. Perez
Summary: A new orally available, potent and selective inhibitor of interleukin-1 beta has been discovered, showing promising results in reducing disease severity and efficacy in a mouse endotoxic shock model.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Alexander Schnitzler, Karsten Niefind
Summary: CK2, a Ser/Thr kinase, has a specific acidic substrate recognition sequence and is inhibited by polyanionic substances like heparin. This study describes the crystal structures of CK2 in complex with different heparin fragments, which provide insights into the inhibitory mechanism of heparin fragments and their chain length-dependent efficacy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Lorena Gonzalez, Lucia Diaz, Joan Pous, Blazej Baginski, Anna Duran-Corbera, Margherita Scarpa, Isabelle Brun-Heath, Ana Igea, Pau Martin-Malpartida, Lidia Ruiz, Chiara Pallara, Mauricio Esguerra, Francesco Colizzi, Cristina Mayor-Ruiz, Ricardo M. Biondi, Robert Soliva, Maria J. Macias, Modesto Orozco, Angel R. Nebreda
Summary: p38 alpha is a versatile protein kinase that plays important roles in cellular stress responses. Dysregulation of p38 alpha signaling is linked to several diseases, making it a potential therapeutic target.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Gordana Scepanovic, Miranda Victoria Hunter, Ran Kafri, Rodrigo Fernandez-Gonzalez
Summary: The research demonstrates that in Drosophila embryos, activation of p38 kinase helps limit wound size and promote rapid wound healing by increasing cell volume around the wound.
Review
Pharmacology & Pharmacy
Charu Chaudhry, Andrew Tebben, S. John Tokarski, Robert Borzilleri, J. William Pitts, Jonathan Lippy, Litao Zhang
Summary: Kinases, which account for 20% of the human genome, have been a major focus in pharmaceutical drug discovery for over three decades. Despite the challenges in identifying novel kinase inhibitors with good properties, the need for diverse and powerful tools in kinase drug discovery is evident in order to efficiently generate highly optimized kinase inhibitors.
DRUG DISCOVERY TODAY
(2021)
Article
Chemistry, Multidisciplinary
Linyao Zhao, Yixuan Wang, Yang Xu, Qian Sun, Hao Liu, Qianxue Chen, Baohui Liu
Summary: The study demonstrated that BIRB796 inhibits proliferation and invasion in GBM cells, suggesting its potential as an adjuvant therapy to enhance the efficacy of GBM treatment.
Article
Biology
Michal Otreba, Johanna Johansson Sjolander, Morten Grotli, Per Sunnerhagen
Summary: The small molecule INR119 enhances the activity of protein kinases in fission yeast and human cells under oxidative stress, with a potential conservation of its mechanism of action between yeast and humans.
Article
Biochemistry & Molecular Biology
Ganesan Senthil Kumar, Rebecca Page, Wolfgang Peti
Summary: The study revealed that the binding of p38 with MKK6 influences helix alpha F and engages not only through its hydrophobic docking groove; Unlike MAPK phosphatases, the p38 conserved docking (CD) site is minimally affected by MKK6 binding; These interactions with p38 are conserved independent of the MKK6 activation state, suggesting differences in specificity markers of p38 regulation by upstream kinases.
Article
Biochemistry & Molecular Biology
K. Chojnacki, D. Lindenblatt, P. Winska, M. Wielechowska, C. Toelzer, K. Niefind, M. Bretner
Summary: New halogenated 1H-triazolo [4,5-b] pyridines and 1H-imidazo [4,5-b] pyridines were synthesized as analogues of known CK2 inhibitors, with di- and trihalogenated 1H-triazolo [4,5-bl] pyridines showing the highest activity against CK2 alpha. Compounds were also evaluated for their effect on the viability of cancer cell lines, and crystal structures of complexes with CK2 alpha and CK2 alpha' were obtained.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Niklas M. Tormaehlen, Mariella Martorelli, Annette Kuhn, Florian Maier, Jamil Guezguez, Michael Burnet, Wolfgang Albrecht, Stefan A. Laufer, Pierre Koch
Summary: This study investigated the blood-brain barrier permeability of Skepinone-based p38 alpha MAP kinase inhibitors and their potential therapeutic effects in neuroinflammation and neurodegeneration. Methyl ester prodrugs were used to enhance oral absorption, resulting in compounds with good brain-to-plasma ratios. These compounds were selective for p38 alpha-MAP kinase, metabolically stable, and able to modulate IL-6 and TNF-alpha production.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Stephanie Cristine Hepp Rehfeldt, Joana Silva, Celso Alves, Susete Pinteus, Rui Pedrosa, Stefan Laufer, Marcia Ines Goettert
Summary: This study evaluated the neuroprotective, antioxidant, and anti-inflammatory activities of luteolin-7-O-glucoside (Lut7). The results suggest that Lut7 has neuroprotective effects and further studies should be conducted to validate its potential in the treatment of neurodegenerative diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Editorial Material
Chemistry, Medicinal
Stefan Laufer, Jurgen Bajorath, Matthias Gehringer, Nathanael Gray, Stephen Frye, Craig W. Lindsley
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Cell Biology
Enni-Kaisa Mustonen, Tatu Pantsar, Azam Rashidian, Juliander Reiner, Matthias Schwab, Stefan Laufer, Oliver Burk
Summary: This study aimed to identify small-molecule kinase inhibitors that can also act as PXR antagonists. Through computational screening and experimental validation, four novel PXR antagonists and one agonist were identified. Further experiments showed that these compounds can directly bind to PXR and disrupt its interaction with coregulatory proteins.
Article
Chemistry, Medicinal
Michael Juchum, Bent Pfaffenrot, Philip Klovekorn, Roland Selig, Wolfgang Albrecht, Lars Zender, Stefan A. Laufer
Summary: MKK4 has been identified as a druggable target for the treatment of acute liver failure, and its inhibitors can promote liver regeneration or reduce hepatocyte death. However, the selectivity of existing potent inhibitors is highly sensitive to minor modifications of the molecule, requiring a careful balance between potency and selectivity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Darius P. Zlotos, Thales Kronenberger, Stefan A. Laufer
Summary: Hormone-dependent cancers, such as certain types of breast cancer, can be treated with anticancer drug conjugates that combine estrogen receptor (ER) ligands with other anticancer agents. These conjugates not only have dual action at anti-cancer targets, but also selectively deliver cytotoxic agents to ER-positive tumor cells, reducing toxicity and adverse effects. They can also overcome resistance to anti-hormonal monotherapy. This review discusses the design, structures, and pharmacological effects of various drug conjugates containing ER ligands linked to diverse anticancer agents.
Article
Pharmacology & Pharmacy
Thomas Pflieger, Rakesh Venkatesh, Markus Dachtler, Karin Eggenreich, Stefan Laufer, Dominique Lunter
Summary: This study applied SAOS rheology to investigate the formulation of the antihypertensive drug Metoprolol Succinate (MSN) in two carrier polymers for pharmaceutical 3D printing. The findings provided a better understanding of the extrudability and thermal durability of the pharmaceutical formulation, which is crucial for developing an approved printing process.
Article
Chemistry, Medicinal
Nadine Kruger, Thales Kronenberger, Hang Xie, Cheila Rocha, Stefan Pohlmann, Haixia Su, Yechun Xu, Stefan A. A. Laufer, Thanigaimalai Pillaiyar
Summary: The development of direct-acting antiviral drugs is necessary due to the COVID-19 pandemic caused by SARS-CoV-2. In this study, natural products were tested for their ability to inhibit the main protease M-pro of SARS-CoV-2. Some compounds were found to effectively inhibit M-pro and exhibited antiviral properties without cytotoxicity. The compound robinetin was able to form a covalent interaction with the catalytic site of M-pro.
Article
Chemistry, Medicinal
Jean Quancard, Anna Vulpetti, Anders Bach, Brian Cox, Stephanie M. Gueret, Ingo V. Hartung, Hannes F. Koolman, Stefan Laufer, Josef Messinger, Gianluca Sbardella, Russell Craft
Summary: Hit generation is a crucial step in drug discovery that determines the speed and success rate of identifying drug candidates. Different strategies are available for identifying chemical starting points for each biological target. This article discusses the best practices for target-centric hit generation, validation of hits, and the design of integrated strategies to maximize the chance of identifying high-quality starting points.
Review
Biochemistry & Molecular Biology
Leon Katzengruber, Pascal Sander, Stefan Laufer
Summary: MKK4 is a dual-specificity protein kinase that regulates JNK and p38 MAPK signaling pathways, impacting cell proliferation, differentiation, and apoptosis. It is overexpressed in aggressive cancer types and plays a key role in liver regeneration. MKK4 is a promising target for cancer therapeutics and the treatment of liver-associated diseases. Recent progress in MKK4 drug discovery and the interest from a startup company highlight its importance in drug development.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Debora Bublitz Anton, Julia Galvez Bulhoes Pedreira, Maria Luiza Zvirtes, Stefan A. Laufer, Rodrigo Gay Ducati, Marcia Goettert, Luis Fernando Saraiva Macedo Timmers
Summary: The SARS-CoV-2 virus has caused a global pandemic, infecting over 688 million people and resulting in around 6.8 million deaths. The virus induces lung inflammation and the release of pro-inflammatory cytokines, making anti-inflammatory therapies important in addition to antiviral drugs. The main protease (MPro) of SARS-CoV-2 is a potential drug target as it is essential for viral replication. In this study, six kinase inhibitors were evaluated for their inhibitory activity against SARS-CoV-2 MPro, and BIRB-796 and Baricitinib were identified as potential inhibitors with dual antiviral and anti-inflammatory activity.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Review
Chemistry, Medicinal
Valentin R. Wydra, Raphael B. Ditzinger, Nico J. Seidler, Frederik W. Hacker, Stefan A. Laufer
Summary: This article summarizes newly patented MAPK inhibitors from 2018 to early 2023, providing information on the patents, corresponding publications, development process, and clinical trials involving these compounds. Recently reported inhibitors show excellent selectivity and even achieve selectivity between closely related isoforms. This progress offers the possibility of eliminating unwanted side effects and may lead to the approval of the first MAPK inhibitor.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2023)
Article
Biochemistry & Molecular Biology
Fatma Al-Rubaiai, Zakiya Zahran Al-Shariqi, Khalsa S. Al-Shabibi, John Husband, Asmaa M. Al-Hattali, Marcia Goettert, Stefan Laufer, Younis Baqi, Syed Imran Hassan, Majekodunmi O. Fatope
Summary: Maytenus dhofarensis Sebsebe is a shrub native to Oman that causes shivering attacks on grazed goats. Chemical investigation of its fruits and stems led to the discovery of new compounds, including a sesquiterpene pyridine alkaloid and lignanolactone. The structures and relative configurations of these compounds were determined through various analytical techniques. One of the compounds showed no inhibition activity on a kinase enzyme, while another compound exhibited strong antioxidant activity.
Article
Chemistry, Medicinal
Julian Laux, Mariella Martorelli, Simon Strass, Dieter Schollmeyer, Florian Maier, Michael Burnet, Stefan A. Laufer
Summary: This study investigated the distribution of small molecule pharmacology in blood, organs, and cells using fluorescent ligands. The results showed that the substance was mainly associated with granules or organelles, and azalide macrolides concentrated in lung and gut epithelia. These findings suggest that current estimation methods may underestimate the drug concentration in mucous membranes.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Chemistry, Medicinal
Karoline B. Waitman, Larissa C. de Almeida, Marina C. Primi, Jorge A. E. G. Carlos, Claudia Ruiz, Thales Kronenberger, Stefan Laufer, Marcia Ines Goettert, Antti Poso, Sandra V. Vassiliades, Vinicius A. M. de Souza, Monica F. Z. J. Toledo, Neuza M. A. Hassimotto, Michael D. Cameron, Thomas D. Bannister, Leticia Costa-Lotufo, Joa o A. Machado-Neto, Mauricio T. Tavares, Roberto Parise-Filho
Summary: A series of hybrid inhibitors combining pharmacophores of known kinase inhibitors and benzohydroxamate HDAC inhibitors were synthesized and evaluated for their anticancer activity and pharmacokinetic properties. Compounds 4d-f exhibited promising cytotoxicity against hematological cells and moderate activity against solid tumor models. Compound 4d showed potent inhibition of multiple kinase targets and had stable interactions with HDAC and members of the JAK family. These compounds showed selective cytotoxicity with minimal effects on non-tumorigenic cells and favorable pharmacokinetic profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
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)
