Article
Neurosciences
Jun Egawa, Reza K. Arta, Vance P. Lemmon, Melissa Munos-Barrero, Yan Shi, Michihiro Igarashi, Toshiyuki Someya
Summary: Protein kinases play important roles in neuronal development, and poorly characterized kinases may also be involved. This study suggests that cyclin G-associated kinase (GAK) may regulate neurite outgrowth and synaptogenesis, and decreased GAK function could lead to impaired neuronal development.
Article
Cell Biology
Carrow Wells, Yi Liang, Thomas L. Pulliam, Chenchu Lin, Dominik Awad, Benjamin Eduful, Sean O'Byrne, Mohammad Anwar Hossain, Carolina Moura Costa Catta-Preta, Priscila Zonzini Ramos, Opher Gileadi, Carina Gileadi, Rafael M. Counago, Brittany Stork, Christopher G. Langendorf, Kevin Nay, Jonathan S. Oakhill, Debarati Mukherjee, Luigi Racioppi, Anthony R. Means, Brian York, Donald P. McDonnell, John W. Scott, Daniel E. Frigo, David H. Drewry
Summary: This study presents a selective small molecule probe, SGC-CAMKK2-1, that specifically targets CAMKK2, which can be used to investigate the therapeutic benefits of CAMKK2 inhibition.
Editorial Material
Cell Biology
Michael J. Munson, Benan J. Mathai, Matthew Yoke Wui Ng, Laura Trachsel-Moncho, Laura R. de la Ballina, Anne Simonsen
Summary: Maintenance of cellular homeostasis requires the removal of mitochondria through programmed or stress-induced mitophagy. While stress-induced mitophagy is regulated by PRKN, the mechanisms regulating basal mitophagy levels are still poorly understood. Recent research has identified two kinases, GAK and PRKCD, as positive regulators of PRKN-independent mitophagy. PRKCD is found to be localized to mitochondria and regulates the recruitment of ULK1-ATG13 during mitophagy induction. On the other hand, GAK activity modifies mitochondrial and lysosomal morphology, compromising efficient transport of mitochondria for degradation. Impairment of either kinase in vivo blocks basal mitophagy, underscoring the biological significance of these findings.
Article
Medicine, Research & Experimental
Masaya Miyazaki, Masaki Hiramoto, Naoharu Takano, Hiroko Kokuba, Jun Takemura, Mayumi Tokuhisa, Hirotsugu Hino, Hiromi Kazama, Keisuke Miyazawa
Summary: The study revealed that GAK plays a crucial role in controlling lysosomal dynamics through actomyosin regulation, thereby promoting a steady progression of autophagy. Genetic disruption or chemical inhibition of GAK resulted in impaired autophagosome-lysosome fusion and affected the maintenance of lysosomal homeostasis during autophagy. The findings highlight the importance of GAK in regulating lysosomal dynamics in the autophagy-lysosome system.
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
(2021)
Article
Chemistry, Medicinal
Belen Martinez-Gualda, Sirle Saul, Mathy Froeyen, Dominique Schols, Piet Herdewijn, Shirit Einav, Steven De Jonghe
Summary: Inserting a carboxamide residue at position 3 of the scaffold can generate potent GAK inhibitors with antiviral activity against dengue virus.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Editorial Material
Pharmacology & Pharmacy
Marco P. Licciardello, Paul Workman
Summary: Casein kinase 2, a potential therapeutic target in cancer due to its high expression, did not exhibit broad antiproliferative activity in cancer cells when targeted by the new inhibitor SGC-CK2-1, developed by Wells and colleagues.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Mandy Pack, Claudia Goetz, Selina Wrublewsky, Mathias Montenarh
Summary: This study used a new highly specific CK2 inhibitor, SGC-CK2-1, and a well-established inhibitor, CX-4945, to analyze the importance of CK2 in insulin production and secretion from pancreatic beta-cells. Both inhibitors had minimal effects on cell proliferation and viability but increased insulin production and secretion.
Article
Chemistry, Multidisciplinary
Xiaoyun Zhang, Jochen Spiegel, Sergio Martinez Cuesta, Santosh Adhikari, Shankar Balasubramanian
Summary: The CMPP strategy allows for the investigation of DNA G-quadruplex (G4) interactions with proteins in native chromatin. This approach enables the identification of G4-interacting proteins in live cells, providing a chemical strategy to study molecular interactions in cellular chromatin.
Article
Plant Sciences
Liqian Chen, Xinghong Zhou, Yijian Deng, Ying Yang, Xiaohu Chen, Qinghong Chen, Yanyan Liu, Xiuqiong Fu, Hiu Yee Kwan, Yanting You, Wen Jin, Xiaoshan Zhao
Summary: This study aimed to confirm the protective effects of ZWD on cardiac hypertrophy and explore the underlying mechanisms. The results showed that ZWD reduces oxidative stress and inflammation and exerts cardioprotective effects by activating the sGC-cGMP-PKG signaling pathway.
JOURNAL OF ETHNOPHARMACOLOGY
(2023)
Article
Cell Biology
Kanta Yamazoe, Yoshihiro H. Inoue
Summary: The Cdk1-CycB complex is crucial for cell-cycle regulation. Import and export processes are important for the localization and activation of Cdk1. Interaction between Cdc25C and Cdk-activating kinase with Cdk1 in the nucleus is necessary for centrosome separation.
Review
Chemistry, Medicinal
Andreas Gollner, Claudia Heine, Karin S. Hofbauer
Summary: Kinases are important drug targets and chemical probe compounds have played a critical role in understanding their biological pathways. Boehringer Ingelheim's open innovation platform, opnMe.com, provides twelve validated chemical probes that target kinases for free. This article presents a summary of key data and synthesis routes for these compounds, aiming to assist researchers in their usage in scientific research.
Article
Chemistry, Medicinal
Zachary W. Davis-Gilbert, Andreas Kraemer, James E. Dunford, Stefanie Howell, Filiz Senbabaoglu, Carrow I. Wells, Frances M. Bashore, Tammy M. Havener, Jeffery L. Smith, Mohammad A. Hossain, Udo Oppermann, David H. Drewry, Alison D. Axtman
Summary: Naphthyridine-based inhibitors were synthesized to produce a potent and cell active inhibitor of casein kinase 2 (CK2). Compound 2 selectively inhibits CK2 alpha and CK2 alpha ' when broad-profiled, making it an exquisitely selective chemical probe for CK2. A negative control, compound 7, lacking a key hinge-binding nitrogen, was designed based on structural studies and showed excellent kinome-wide selectivity by not binding CK2 alpha or CK2 alpha ' in cells. Compound 2 displayed differential anticancer activity compared to a structurally distinct CK2 chemical probe, SGC-CK2-1.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Multidisciplinary Sciences
Yihu Xie, Christopher L. Lord, Bradley P. Clarke, Austin L. Ivey, Pate S. Hill, W. Hayes McDonald, Susan R. Wente, Yi Ren
Summary: CTDK-1 is the primary RNA Pol II CTD Ser2 kinase complex in budding yeast, consisting of a CDK Ctk1, a cyclin Ctk2, and a unique subunit Ctk3 which activates Ctk1 by stabilizing the T-loop. Additionally, Ctk3 contributes to the assembly of CTDK-1 through interactions with both Ctk1 and Ctk2, and physically interacts with Gbp2, a serine/arginine-like protein. These findings reveal a regulatory mechanism of CDK complexes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Multidisciplinary
Angela Weigert Munoz, Kevin M. Meighen-Berger, Stephan M. Hacker, Matthias J. Feige, Stephan A. Sieber
Summary: This study elucidates the target scope of catechol-containing bioactive molecules from diverse foods and drugs using a mass spectrometry-based competitive chemical proteomics approach. The results reveal that these molecules bind to proteins associated with the endoplasmic reticulum and activate the unfolded protein response, potentially explaining the health-promoting effects of catechol-containing natural products.
Review
Biochemistry & Molecular Biology
Mohammad Faysal Al Mazid, Seung Bin Park, Subba Rao Cheekatla, Dhiraj P. Murale, Kyung Ho Shin, Jun-Seok Lee
Summary: Chemical probes play a crucial role in understanding the biological nature of diseases like cancer. They are widely used to detect cancer-associated proteins, monitor drug efficacy, and study the activity of enzymes and immune cells. This review focuses on the synthesis of chemical probes for different cancer types and their application in various monitoring techniques, including photodynamic therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Albert A. Antolin, Domenico Sanfelice, Alisa Crisp, Eloy Villasclaras Fernandez, Ioan L. Mica, Yi Chen, Ian Collins, Aled Edwards, Susanne Mueller, Bissan Al-Lazikani, Paul Workman
Summary: The Chemical Probes Portal is a public resource for researchers to select and use high-quality chemical probes. Chemical probes are crucial for protein function research and drug discovery, but the use of low-quality probes has led to erroneous conclusions. The portal provides background, principles, content, and technical development, and encourages researcher involvement.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Medicinal
Martin Schroeder, Matthias Leiendecker, Ulrich Graedler, Juliane Braun, Andreas Blum, Marek Wanior, Benedict-Tilman Berger, Andreas Kraemer, Susanne Mueller, Christina Esdar, Stefan Knapp, Timo Heinrich
Summary: The conserved catalytic sites in protein kinases make it difficult to find ATP competitive inhibitors with selectivity for the whole kinome. However, during a fragment campaign for focal adhesion kinase (FAK), a scaffold that lost its initial FAK affinity showed remarkable potency and selectivity for serine-arginine-protein kinases 1-3 (SRPK1-3). Non-conserved interactions with the uniquely structured hinge region of the SRPK family were the key drivers of the exclusive selectivity of the discovered fragment hit.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Cell Biology
Carrow Wells, Yi Liang, Thomas L. Pulliam, Chenchu Lin, Dominik Awad, Benjamin Eduful, Sean O'Byrne, Mohammad Anwar Hossain, Carolina Moura Costa Catta-Preta, Priscila Zonzini Ramos, Opher Gileadi, Carina Gileadi, Rafael M. Counago, Brittany Stork, Christopher G. Langendorf, Kevin Nay, Jonathan S. Oakhill, Debarati Mukherjee, Luigi Racioppi, Anthony R. Means, Brian York, Donald P. McDonnell, John W. Scott, Daniel E. Frigo, David H. Drewry
Summary: This study presents a selective small molecule probe, SGC-CAMKK2-1, that specifically targets CAMKK2, which can be used to investigate the therapeutic benefits of CAMKK2 inhibition.
Article
Biochemistry & Molecular Biology
Claudia Tredup, Benardina Ndreshkjana, Natalie S. Schneider, Amelie Tjaden, Aurino M. Kemas, Sonia Youhanna, Volker M. Lauschke, Benedict-Tilman Berger, Andreas Kraemer, Lena M. Berger, Sandra Roehm, Stefan Knapp, Henner F. Farin, Susanne Mueller
Summary: Well-characterized small molecules are crucial for studying target proteins in biology and therapy. However, many compounds lack the necessary potency and selectivity for mechanistic cellular studies. The donated chemical probe (DCP) library provides an openly available collection of valuable and well-characterized tools, including a systematic description and comprehensive characterization data. It represents a unique resource for the biomedical research community.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mohamed Hasyeoui, Frederic Lassagne, William Erb, Manal Nael, Khaled M. Elokely, Apirat Chaikuad, Stefan Knapp, Adrian Jorda, Soraya L. Vall, Emie Quissac, Maite Verreault, Thomas Robert, Stephane Bach, Ali Samarat, Florence Mongin
Summary: The effects of FL-291 on the viability of neuroblastoma cells were investigated and found to have no significant impact on cell survival. Structural analysis revealed similar binding modes for FL-291 and CD-07 with GSK-3 beta. A library of analogs was designed and synthesized, and the new inhibitor MH-124 exhibited clear selectivity for GSK-3 alpha.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Rohit Arora, Joannes T. M. Linders, Samia Aci-Seche, Thomas Verheyen, Erika Van Heerde, Dirk Brehmer, Apirat Chaikuad, Stefan Knapp, Pascal Bonnet
Summary: The mutation V600E in B-Raf leads to mitogen activated protein kinase (MAPK) pathway activation, uncontrolled cell proliferation, and tumorigenesis. ATP competitive type I B-Raf inhibitors efficiently block the MAPK pathways in B-Raf mutant cells but induce conformational changes in the wild type B-Raf (wtB-Raf) kinase domain causing paradoxical hyperactivation. Type II inhibitors prevent heterodimerization by binding the kinase in the DFG-out conformation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Marcel Rak, Roberta Tesch, Lena M. Berger, Ekaterina Shevchenko, Monika Raab, Amelie Tjaden, Rezart Zhubi, Dimitrios-Ilias Balourdas, Andreas C. Joerger, Antti Poso, Andreas Kra, Lewis Elson, Aleksandar Luc, Thales Kronenberger, Thomas Hanke, Klaus Strebhardt, Mourad Sanhaji, Stefan Knapp
Summary: Salt-inducible kinases 1-3 (SIK1-3) are important regulators of cellular homeostasis. This study presents a structure-based approach to improve the selectivity of inhibitors targeting SIK kinases, resulting in the development of a valuable tool compound, MR22, which showed excellent selectivity and phenotypic effects in ovarian cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Han Wee Ong, Anna Truong, Frank Kwarcinski, Chandi de Silva, Krisha Avalani, Tammy M. Havener, Michael Chirgwin, Kareem A. Galal, Caleb Willis, Andreas Kramer, Shubin Liu, Stefan Knapp, Emily R. Derbyshire, Reena Zutshi, David H. Drewry
Summary: Malaria is a global health problem with high morbidity and mortality rates. The emergence of drug resistance against current treatments emphasizes the need for alternative antimalarials. In this study, we discovered Ki8751 as an inhibitor of essential kinase PfPK6 and identified two compounds (67 and 79) with potent antiplasmodial activity against both blood and liver stages of malaria.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Xiaomin Ni, Andreas C. Joerger, Apirat Chaikuad, Stefan Knapp
Summary: FUBP-interacting repressor (FIR) is a suppressor of the proto-oncogene MYC's transcription, by binding to the far upstream element (FUSE) of the MYC promoter. Competition with FUSE-binding protein 1 (FUBP1) is a crucial mechanism for MYC transcriptional regulation.
Review
Oncology
Khoa Nguyen, Julia Boehling, Minh N. Tran, Thomas Cheng, Andrew Rivera, Bridgette M. Collins-Burow, Sean B. Lee, David H. Drewry, Matthew E. Burow
Summary: Kinases are biomolecules essential for cellular reactions, but disruptions in their expression and activity can lead to diseases like cancer. Though significant progress has been made, a large portion of the human kinome remains understudied. This review focuses on the understudied NEK family of kinases, discussing existing studies, gene expression correlations with patient survival, NEK mutations in different cancer tissues, and potential funding opportunities.
Article
Oncology
Jiung Nam, Amelia U. Schirmer, Chelsea Loh, David H. Drewry, Everardo Macias
Summary: Breast cancer is the most common type of cancer in women, and its treatment is often associated with cardiovascular toxicity. This study explores the potential of targeting the protein kinase STK3 in breast cancer therapy and cardioprotection. STK3 is amplified in breast cancer and is associated with worse patient outcomes, suggesting a noncanonical pro-tumorigenic role. Different breast cancer cell lines have varying dependence on STK3, and its inhibition has shown therapeutic effects in suppressing cancer growth and protecting cardiomyocytes from the toxic effects of chemotherapy. STK3 inhibition does not interfere with the therapeutic efficacy of doxorubicin. This research highlights the potential of STK3 as a molecular target for breast cancer treatment, offering dual therapeutic effects.
Article
Oncology
Leonore Novak, Maria Petrosino, Alessandra Pasquo, Apirat Chaikuad, Roberta Chiaraluce, Stefan Knapp, Valerio Consalvi
Summary: ERK2 is a key player in the Ras-Raf-MEK-ERK signal transduction cascade and its variants in the common docking site have been found in cancer tissues. This study provides a comprehensive analysis of the structural, functional, and stability data of ERK2 wild-type and variants. Understanding the impact of single nucleotide variations on ERK2 can help design alternative therapies and move towards personalized medicine.
Article
Cell Biology
Laura M. Meyer, Sebastian E. Koschade, Jonas B. Vischedyk, Marlyn Thoelken, Andrea Gubas, Martin Wegner, Marion Basoglu, Stefan Knapp, Manuel Kaulich, Stefan Eimer, Shabnam Shaid, Christian H. Brandts
Summary: The selective degradation of mitochondria through mitophagy is crucial for maintaining mitochondrial homeostasis and disease progression in acute myeloid leukemia (AML). In this study, a pairwise multiplexed CRISPR screen targeting mitophagy receptors revealed OPTN as the sole non-redundant mitophagy receptor in AML. OPTN was found to be rate-limiting for AML cell proliferation, and its loss extended overall median survival in a murine transplantation model. Mechanistically, OPTN deficiency impaired mitochondrial respiration and function, leading to increased mitochondrial ROS and a proliferation defect. These findings provide insights into the network of mitophagy receptors in AML and suggest OPTN inhibition as a potential therapeutic strategy.
Article
Cell Biology
Chanchal Chauhan, Andreas Kraemer, Stefan Knapp, Mark Windheim, Alexey Kotlyarov, Manoj B. Menon, Matthias Gaestel
Summary: This study investigates the role of MAPK-activated protein kinase 2 (MK2) in cell death and identifies 5-Iodotubercidin (5-ITu) as a potent compound that sensitizes MK2-deficient cells to TNF-induced death. It is found that 5-ITu induces RIPK1-dependent necroptosis by suppressing IKK signaling in the absence of MK2 activity.
CELL DEATH DISCOVERY
(2023)
