Editorial Material
Biochemistry & Molecular Biology
Bernd Pulverer
Summary: Starting from 2024, The EMBO Journal and EMBO Reports will join EMBO Molecular Medicine, Molecular Systems Biology, and Life Science Alliance as Open Access journals, taking another step towards the goal of an integrated Open Science approach for disseminating highly selected and curated science.
Review
Chemistry, Multidisciplinary
Md Kabir, Xufen Yu, H. Umit Kaniskan, Jian Jin
Summary: Proteolysis-targeting chimeras (PROTACs) are small molecules that induce targeted degradation of proteins by forming ternary complexes with E3 ligases. They have the advantage of targeting both canonical and noncanonical functions of epigenetic targets, resulting in greater therapeutic efficacy. This review analyzes published PROTAC degraders of epigenetic writer, reader, and eraser proteins and discusses their mechanism of action and advantages in cancer treatment. Overall, pharmacological degradation of epigenetic targets has emerged as an effective strategy against cancer.
CHEMICAL SOCIETY REVIEWS
(2023)
Review
Chemistry, Multidisciplinary
Sam Benson, Fabio de Moliner, William Tipping, Marc Vendrell
Summary: Recent progress in optical bioimaging has led to the demand for minimal chemical reporters that can preserve the properties and activities of biomolecules. Various approaches have been developed to reduce the size of fluorescent and Raman labels to a few atoms and incorporate them into building blocks to form native-like supramolecular structures. This integration of small optical reporters into biomolecules has enabled the creation of previously inaccessible smart molecular entities, greatly expanding their applications in biological imaging.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
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)
Review
Pharmacology & Pharmacy
Esra Balikci, Anne-Sophie M. C. Marques, Jesper S. Hansen, Kilian V. M. Huber
Summary: The rational development of new therapeutics requires a thorough understanding of how aberrant signaling affects cellular homeostasis and causes human disease. Chemical probes are powerful tools for drug discovery that have led to fundamental insights into biological processes and have paved the way for the development of first-in-class drugs.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Article
Chemistry, Multidisciplinary
Jianyu Hu, Jing Zhou, Rui Liu, Yi Lv
Summary: A novel element probe based CRISPR/Cas14 detection platform was proposed in this study, allowing sensitive and quantitative detection of non-nucleic-acid targets such as trace aqueous ampicillin within 45 minutes at room temperature. The method showed excellent performance in anti-interference tests and complex matrix detection, with a low detection limit of 2.06 nM.
CHEMICAL COMMUNICATIONS
(2021)
Review
Chemistry, Organic
Nora Khiar-Fernandez, Jon Macicior, Beatriz Marcos-Ramiro, Silvia Ortega-Gutierrez
Summary: Chemical probes in specific applications in chemical biology and medicinal chemistry have greatly enhanced our understanding of biological systems, with fundamental implications for the development of new therapeutic strategies. Successful drug discovery programs now prioritize identification, engagement, and endogenous levels of therapeutic targets from the earliest stages.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Fahad Hussain Mohammed, Franz Cemic, Joergen Hemberger, Shibashish Giri
Summary: Epigenetic regions such as VEGF, EGFR, TGFb, DNMTs, HDAC1/2, and miRNA are innovative druggable targets for building a novel platform of drugs for preventive and regenerative skin health care. Clinical and preclinical trials are being conducted for skin regeneration using epigenetic-based small molecules. Epigenetic writers, eraser targets, and epigenetic readers will play a crucial role in skin regenerative therapy in the near future.
DRUG DISCOVERY TODAY
(2023)
Review
Oncology
Carolyn J. Kravitz, Qin Yan, Don X. Nguyen
Summary: In recent years, it has been discovered that histone and DNA modifying enzymes play a role in different stages of metastasis. Epigenomic alterations can now be measured and detected in human tumors or liquid biopsies. Alterations in the epigenome may cause a loss in lineage integrity, leading to the development of malignant cell clones with a proclivity for relapse. Genetic aberrations acquired during tumor progression or therapeutic response, as well as the evolution of the stroma, can also contribute to these alterations. This review emphasizes the importance of leveraging chromatin and DNA modifying mechanisms as biomarkers and therapeutic targets for metastatic cancers.
CANCER AND METASTASIS REVIEWS
(2023)
Article
Chemistry, Multidisciplinary
Louis P. Conway, Appaso M. Jadhav, Rick A. Homan, Weichao Li, Juanita Sanchez Rubiano, Richard Hawkins, R. Michael Lawrence, Christopher G. Parker
Summary: The study systematically evaluated several diazirine-containing FF tags and found that these tags have profound effects on the proteomic profiles of chemical probes.
Article
Biochemistry & Molecular Biology
Yunlong Shi, Kate S. Carroll
Summary: This study evaluates nucleophilic and electrophilic chemical probes for Cys-SOH, demonstrating that a probe based on the norbornene scaffold does not react with validated sulfenic acid models and that purported cross-reactivity of dimedone-like probes with electrophiles is not meaningful in a biological setting. Nucleophilic probes remain the most viable tools for bioorthogonal detection of Cys-SOH.
Review
Chemistry, Multidisciplinary
Yusheng Xie, Shubo Du, Zhiyang Liu, Min Liu, Zhiqiang Xu, Xiaojie Wang, Jia Xuan Kee, Fan Yi, Hongyan Sun, Shao Q. Yao
Summary: Lysine acylation plays pivotal roles in cell physiology and dysregulated lysine acylation is closely involved in the pathophysiological progress of many human diseases. Chemical biology tools have advanced the study of lysine acylation and its regulatory proteins, leading to the discovery of ligands for targeting regulators of lysine acylation. However, there are still challenges and a need for more discriminating chemical probes in future studies of post-translational modifications.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Review
Chemistry, Medicinal
Dheeraj Pandey, Tiyas Pal, Abha Sharma, S. J. S. Flora
Summary: This article discusses the importance of epigenetics in Alzheimer's disease, suggesting that various epigenetic targets may provide new insights into potential therapeutic approaches for AD.
MINI-REVIEWS IN MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Inkyung Jung, Jungeun An, Myunggon Ko
Summary: Epigenetic modifications play crucial roles in gene expression regulation and are commonly dysregulated in cancers, influencing cell lineage differentiation, survival, and proliferation. Aberrant epigenetic modifications confer unique characteristics to tumor cells, leading to sustained proliferation, resistance to growth-suppressive or cell death signals, replicative immortality, invasion, and metastasis. DNA cytosine methylation-demethylation, among various epigenetic mechanisms in mammals, is frequently disrupted in cancers. Targeting DNA methylation dynamics has gained attention as a promising therapeutic approach to restore normal conditions affected by cancer-specific epigenetic abnormalities. Small molecules targeting DNA (de)methylation regulators have been developed as potential cancer therapeutics, with some already approved for clinical usage and many others undergoing clinical trials.
Review
Oncology
Jaewang Lee, Jong-Lyel Roh
Summary: Ferroptosis is an oxidative-regulated cell death caused by iron-mediated lipid peroxidation accumulation. Radical-trapping antioxidant systems can eliminate oxidized lipids to maintain cell membrane integrity. Epigenetic modifications, such as DNA methylation and histone modifications, can regulate ferroptosis by altering gene expression or cell phenotype. Understanding the epigenetic alterations in cancer can help overcome therapeutic resistance and discover new targets for anticancer therapy.
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
Biochemistry & Molecular Biology
Martin P. Schwalm, Stefan Knapp, Vladimir V. Rogov
Summary: Induction of LC3/GABARAP protein interactions with target proteins by small molecules has the potential for targeted protein degradation, but no potent ligands have been developed despite intensive screening campaigns in the past 5 years, limiting its therapeutic applications.
JOURNAL OF CELLULAR BIOCHEMISTRY
(2023)
Article
Chemistry, Medicinal
Serah W. Kimani, Julie Owen, Stuart R. Green, Fengling Li, Yanjun Li, Aiping Dong, Peter J. Brown, Suzanne Ackloo, David Kuter, Cindy Yang, Miranda MacAskill, Stephen Scott MacKinnon, Cheryl H. Arrowsmith, Matthieu Schapira, Vijay Shahani, Levon Halabelian
Summary: DCAF1 serves as a subunit for RING-type CRL4(DCAF1) and HECT family EDVPDCAF1 E3 ubiquitin ligases in substrate recruitment. The WDR domain of DCAF1 acts as a binding platform for substrate proteins and is targeted by HIV and SIV lentiviral adaptors. This study used a proteome-scale drug-target interaction prediction model to identify ligands for the DCAF1 WDR domain through biophysical screening and X-ray crystallography, confirming the selective binding of a predicted ligand. The findings demonstrate the successful application of artificial intelligence-enabled virtual screening methods in the absence of previously known ligands.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(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: Inhibiting a single kinase isoform is difficult due to the similarity of ATP-binding sites. Through studying crystal structures, a highly selective inhibitor for CK1 & epsilon; (SR-4133) was developed. The mismatch between SR-4133 and CK1 & delta; destabilizes their interaction, while the hydrophobic surface of CK1 & epsilon; enhances the binding of SR-4133, leading to selective inhibition. These potent CK1 & epsilon;-selective inhibitors exhibit nanomolar growth inhibition in bladder cancer cells and inhibit the phosphorylation of 4E-BP1, a downstream effector of CK1 & epsilon;.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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
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
Chemistry, Medicinal
Emmanuel Deau, Mattias F. F. Lindberg, Freideiric Miege, Didier Roche, Nicolas George, Pascal George, Andreas Kra''mer, Stefan Knapp, Laurent Meijer
Summary: Dual-specificity,tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) have been identified as important targets for various pathologies. In this study, a family of DYRK/CLK inhibitors called Leucettinibs, derived from Leucettines and Leucettamine B, were synthesized and characterized. These inhibitors showed subnanomolar IC50 on DYRK1A and demonstrated potential for therapeutic drug development. Kinase-inactive isomers, iso-Leucettinibs, were also synthesized as suitable negative control compounds. Leucettinibs were found to inhibit DYRK1A substrate phosphorylation in cells.
JOURNAL OF MEDICINAL CHEMISTRY
(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
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.
