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)
Article
Pharmacology & Pharmacy
Siyuan Tang, Miguel Garzon Sanz, Oliver Smith, Andreas Kraemer, Daniel Egbase, Paul W. Caton, Stefan Knapp, Sam Butterworth
Summary: The cofactor NAD thorn plays a crucial role in physiological processes and enhancing healthy aging. Recent studies have shown that NAMPT activators can increase NAD thorn levels and have beneficial effects. The structure activity relationships of these activators were evaluated and it was hypothesized that they act via a through-water interaction in the NAMPT active site, leading to the design of a urea-class NAMPT activator with similar or greater activity compared to known analogues.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Chemistry, Multidisciplinary
Vaclav Nemec, Prashant Khirsariya, Pavlina Janovska, Paula Martin Moyano, Lukas Maier, Petra Prochazkova, Pavlina Kebkova, Tomas Gybel', Benedict-Tilman Berger, Apirat Chaikuad, Maria Reinecke, Bernhard Kuster, Stefan Knapp, Vitezslav Bryja, Kamil Paruch
Summary: In this study, a new class of potent and highly selective inhibitors of CK1 alpha, delta and epsilon were identified. MU1250, MU1500 and MU1742 were selected as quality chemical probes for those CK1 isoforms due to their optimal in vitro and in vivo profiles and exclusive selectivity. Furthermore, it was found that the central 1H-pyrrolo[2,3-b]pyridine-imidazole pharmacophore can be used as the basis of highly selective inhibitors of other therapeutically relevant protein kinases, such as p38 alpha.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(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
Xuan Yang, Jeffery L. Smith, Michael T. Beck, Jennifer M. Wilkinson, Ani Michaud, James D. Vasta, Matthew B. Robers, Timothy M. Willson
Summary: PLK1 is a protein kinase that regulates mitosis and is an important target for oncology drugs and potential antitarget for drugs against DNA damage response pathway or anti-infective host kinases. A new energy transfer probe called Probe 11 was developed to include PLK1 in live cell NanoBRET target engagement assays. This probe enabled the measurement of potency of known PLK inhibitors and investigation of the promiscuity of adavosertib as a dual PLK1/WEE1 inhibitor. The results showed selective engagement of WEE1 at clinically relevant doses.
Article
Chemistry, Medicinal
Jennifer A. Amrhein, Guiqun Wang, Benedict-Tilman Berger, Lena M. Berger, Amalia D. Kalampaliki, Andreas Kraemer, Stefan Knapp, Thomas Hanke
Summary: Bone morphogenetic protein (BMP) signaling is mediated by heterotetramers formed by type-I and type-II receptors. Upon BMP binding, the constitutively active type-II receptors activate type-I receptors, leading to SMAD effector protein phosphorylation. Most drug development on receptor tyrosine kinase-like (TKL) family has focused on targeting type-I receptors, with only a few inhibitors against type-II receptors. BMPR2 is involved in multiple diseases, including pulmonary arterial hypertension, Alzheimer's disease, and cancer. This study reports the development of a selective and potent BMPR2 inhibitor 8a through macrocyclization of a promiscuous inhibitor 1 based on a 3-amino-1H-pyrazole hinge binding moiety.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Multidisciplinary Sciences
Thaila Fernanda dos Reis, Patricia Alves de Castro, Rafael Wesley Bastos, Camila Figueiredo Pinzan, Pedro F. N. Souza, Suzanne Ackloo, Mohammad Anwar Hossain, David Harold Drewry, Sondus Alkhazraji, Ashraf S. Ibrahim, Hyunil Jo, Jorge D. Lightfoot, Emily M. Adams, Kevin K. Fuller, William F. deGrado, Gustavo H. Goldman
Summary: This study demonstrates the synergistic activity of the host defense peptide mimetic brilacidin with caspofungin against various fungal strains, including those that are resistant to caspofungin. These findings suggest that the combination of brilacidin with antifungal drugs currently in clinical use can improve the treatment outcome of aspergillosis and other fungal infections.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Frances M. M. Bashore, Ariana B. B. Marquez, Apirat Chaikuad, Stefanie Howell, Andrea S. S. Dunn, Alvaro A. A. Beltran, Jeffery L. L. Smith, David H. H. Drewry, Adriana S. S. Beltran, Alison D. D. Axtman
Summary: Tau tubulin kinase 1 and 2 (TTBK1/2) are highly homologous kinases that play important roles in brain-related pathways. TTBK1 is involved in diseases like Alzheimer's disease and amyotrophic lateral sclerosis, while TTBK2 is critical for cilia assembly. In this study, a targeted library was designed to identify chemical tools that can inhibit TTBK1 and TTBK2 and affect downstream signaling. Compound 10 was found to significantly reduce primary cilia expression in human induced pluripotent stem cells (iPSCs), confirming the role of TTBK2 in ciliogenesis.
SCIENTIFIC REPORTS
(2023)
Review
Biochemistry & Molecular Biology
Brian Anderson, Peter Rosston, Han Wee Ong, Mohammad Anwar Hossain, Zachary W. Davis-Gilbert, David H. Drewry
Summary: This article analyzes data on human kinases, including citation count, availability of chemical probes, approved and investigational drugs, PDB structures, and biochemical and cellular assays. The analysis reveals that many kinases are understudied and there is untapped potential for further development. The article also discusses different strategies for generating selectivity between kinases. In conclusion, the authors believe it is possible to develop a tool compound for every human kinase.
BIOCHEMICAL JOURNAL
(2023)
Article
Chemistry, Multidisciplinary
Silvia Arifi, Julian A. Marschner, Julius Pollinger, Laura Isigkeit, Pascal Heitel, Astrid Kaiser, Lennart Obeser, Georg Hoefner, Ewgenij Proschak, Stefan Knapp, Apirat Chaikuad, Jan Heering, Daniel Merk
Summary: The lipid-sensing transcription factor PPAR γ can bind to antidiabetic TZD drugs, oxidized vitamin E metabolites, and vitamin E mimetic garcinoic acid. While the effects of the second binding on PPAR γ activity are unclear, a selective ligand of the second site has been developed, revealing potential noncanonical regulation of PPAR γ activities. This alternative binding diminishes FOXO signaling and may have therapeutic applications.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
News Item
Biochemistry & Molecular Biology
Stefan Knapp, Susanne Mueller
Summary: The quality and appropriate use of chemical tools play a crucial role in determining the quality and reliability of scientific data based on their utilization. Two papers now extend criteria to new modalities and critically review adherence to established guidelines.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Janice M. Reimer, Andrea M. Dickey, Yu Xuan Lin, Robert G. Abrisch, Sebastian Mathea, Deep Chatterjee, Elizabeth J. Fay, Stefan Knapp, Matthew D. Daugherty, Samara L. Reck-Peterson, Andres E. Leschziner
Summary: Leucine Rich Repeat Kinase 1 and 2 (LRRK1 and LRRK2) are homologs in the ROCO family of proteins in humans. Despite their shared domain architecture and involvement in intracellular trafficking, they have strikingly different disease associations, with LRRK2 linked to Parkinson's disease and LRRK1 linked to bone diseases.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Xuan Yang, Han Wee Ong, Rebekah J. Dickmander, Jeffery L. Smith, Jason W. Brown, William Tao, Edcon Chang, Nathaniel J. Moorman, Alison D. Axtman, Timothy M. Willson
Summary: During the development of analogues of 3-cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines, it was discovered that phase II conjugation by GST enzymes played a major role in the metabolic transformation in hepatocytes. A protocol involving co-dosing with ethacrynic acid was developed to enhance the exposure of the analogues in mice.
Article
Biochemistry & Molecular Biology
Martin P. Schwalm, Andreas Kraemer, Anja Doelle, Janik Weckesser, Xufen Yu, Jian Jin, Krishna Saxena, Stefan Knapp
Summary: Cell-based assays using NanoLuciferase and HaloTag were developed to measure the kinetics and stability of PROTAC-induced degradation and ternary complex formation. Characterization of PROTACs targeting WDR5 revealed the importance of ternary complex formation and stability in the early degradation cascade. Comparison of ternary complex crystal structures highlighted the significance of an efficient E3-target interface for ternary complex stability. This study provides a strategy for the rational optimization of PROTACs using a series of live cell assays monitoring key steps of the early PROTAC-induced degradation pathway.
CELL CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Jun Yong Choi, Yoshihiko Noguchi, James M. Alburger, Simon Bayle, Eugene Chung, Wayne Grant, Apirat Chaikuad, Stefan Knapp, Derek R. Duckett, William R. Roush
Summary: Specific inhibition of a single kinase isoform is challenging due to the high conservation of ATP-binding sites. A potent and highly CK1 epsilon-isoform-selective inhibitor (SR-4133) was developed by comparing the X-ray crystal structures of CK1 delta and CK1 epsilon. The selective inhibition of CK1 epsilon is achieved by the stable binding of SR-4133 in the ATP-binding pocket of CK1 epsilon.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Maria Karelou, Dionysis Kampasis, Amalia D. Kalampaliki, Leentje Persoons, Andreas Kraemer, Dominique Schols, Stefan Knapp, Steven De Jonghe, Ioannis K. Kostakis, Sotiris S. Nikolaropoulos
Summary: Sixteen new 2-substituted quinazolines were synthesized and evaluated for their anti-proliferative activity against multiple cancer cell lines. Compound 17 showed remarkable activity against the majority of tested cell lines.
