Article
Biochemistry & Molecular Biology
Martina Pierri, Erica Gazzillo, Maria Giovanna Chini, Maria Grazia Ferraro, Marialuisa Piccolo, Francesco Maione, Carlo Irace, Giuseppe Bifulco, Ines Bruno, Stefania Terracciano, Gianluigi Lauro
Summary: A well-structured in silico workflow is reported for discovering structure-based pharmacophore models against BRD9, accelerating virtual screening and facilitating the identification of novel binders.
BIOORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Ester Colarusso, Sara Ceccacci, Maria Chiara Monti, Erica Gazzillo, Assunta Giordano, Maria Giovanna Chini, Maria Grazia Ferraro, Marialuisa Piccolo, Dafne Ruggiero, Carlo Irace, Stefania Terracciano, Ines Bruno, Giuseppe Bifulco, Gianluigi Lauro
Summary: Targeting bromodomain-containing protein 9 (BRD9), a set of 2,4,5-trisubstituted-2,4-dihydro-3H- 1,2,4-triazol-3-one-based compounds was investigated for the development of new anticancer agents. Through in silico studies, chemical synthesis, biophysical and biological evaluation, compounds with promising selectivity and binding affinity for BRD9 were identified. The multidisciplinary approach used in this study accelerated the selection process and provided insights for the synthesis of novel BRD9 binders.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Lin Yang, Wenbin Tu, Liyue Huang, Bukeyan Miao, Atsunori Kaneshige, Wei Jiang, Lingying Leng, Meilin Wang, Bo Wen, Duxin Sun, Shaomeng Wang
Summary: Researchers have designed and synthesized selective SMARCA2 protein degraders using PROTAC technology, leading to the discovery of potent and selective SMARCA2 degraders such as SMD-3040. SMD-3040 effectively degrades SMARCA2 protein with high selectivity over SMARCA4 protein. It demonstrates strong cell growth inhibitory activity in SMARCA4-deficient cancer cells and exhibits significant tumor growth inhibition in SMARCA4-deficient xenograft models.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Rosa Cookson, Aini Vuorinen, Jonathan Pettinger, Cassandra R. Kennedy, Joanna M. Kirkpatrick, Rachel E. Peltier-Heap, Andrew Powell, Ambrosius P. Snijders, Mark Skehel, David House, Katrin Rittinger, Jacob T. Bush
Summary: Chemoproteomics is a method that can detect interactions between small molecules and the proteome. In this study, a chemoproteomics workflow was developed to screen cysteine-reactive covalent fragments against deubiquitinating enzymes in cell lysates. The workflow was optimized for target identification and covalent fragment library profiling in a 96-well plate format.
CELL REPORTS PHYSICAL SCIENCE
(2023)
Article
Chemistry, Multidisciplinary
Di Zhu, Sandra Johannsen, Tiziana Masini, Celine Simonin, Jorg Haupenthal, Boris Illarionov, Anastasia Andreas, Mahendra Awale, Robin M. Gierse, Tridia van der Laan, Ramon van der Vlag, Rita Nasti, Mael Poizat, Eric Buhler, Norbert Reiling, Rolf Mueller, Markus Fischer, Jean-Louis Reymond, Anna K. H. Hirsch
Summary: In this manuscript, the authors successfully used ligand-based virtual screening (LBVS) to identify two small-molecule drug-like hit classes with excellent ADMET profiles against the challenging microbial enzyme DXPS. They introduced the concept of pseudo-inhibitors to overcome the limitations of standard computer-aided drug design tools for targets with large, hydrophilic binding sites. The hits displayed promising in vitro and whole-cell activity against M. tuberculosis DXPS, and possess unique mechanisms of inhibition, making them potential starting points for the development of antibiotics with a novel mode of action.
Article
Chemistry, Medicinal
Zhiqiang Sun, Bulian Deng, Zichao Yang, Ruiyao Mai, Junli Huang, Zeli Ma, Ting Chen, Jianjun Chen
Summary: This study designed and synthesized a series of HDAC8 degraders based on the PROTAC strategy. Among them, compound ZQ-23 exhibited significant and selective degradation of HDAC8 and achieved maximal degradation effect at a specific time point after treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Liuyu Hu, Yipei Gu, Ju Liang, Mengmeng Ning, Junli Yang, Yi Zhang, Hui Qu, Yaxi Yang, Ying Leng, Bing Zhou
Summary: Nonalcoholic steatohepatitis (NASH) is a progressive stage of nonalcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, hepatocyte ballooning, and fibrosis. Thyroid hormone receptor beta (THR-beta) is emerging as an effective molecular target for NASH treatment, but minimizing adverse effects mediated by thyroid hormone receptor alpha (THR-alpha) is necessary.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biology
Xingang Liu, Wenying Yan, Songsong Wang, Ming Lu, Hao Yang, Xu Chai, He Shi, Yang Zhang, Qingzhong Jia
Summary: A multi-layer virtual screening workflow was established to screen compounds with inhibitory activity against HDAC6 and anti-tumor cell proliferation. The screened compounds showed nanomolar inhibitory activity and anti-proliferative activities against tumor cells, providing novel scaffolds for subsequent anti-tumor drug design based on HDAC6 target.
COMPUTERS IN BIOLOGY AND MEDICINE
(2023)
Article
Chemistry, Medicinal
Barbara Preti, Anna Suchankova, Giuseppe Deganutti, Michele Leuenberger, Kerry Barkan, Iga Manulak, Xianglin Huang, Sabrina Carvalho, Graham Ladds, Martin Lochner
Summary: A series of benzyloxy and phenoxy derivatives of adenosine receptor agonists were synthesized, and their potency and selectivity were evaluated. The compounds with a halogen substituent in the meta position showed the highest potency. NECA-based compounds demonstrated greater A1R selectivity compared to adenosine-based compounds, with certain compounds exhibiting significantly improved selectivity. The presence of a halogen substituent in the benzyloxy or phenoxy group seemed to contribute to high affinity for A1R. Molecular modeling studies suggested the involvement of a hydrophobic subpocket in the observed A1R selectivity.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Xueping Hu, Jinping Pang, Jintu Zhang, Chao Shen, Xin Chai, Ercheng Wang, Haiyi Chen, Xuwen Wang, Mojie Duan, Weitao Fu, Lei Xu, Yu Kang, Dan Li, Hongguang Xia, Tingjun Hou
Summary: Different ligands binding to the glucocorticoid receptor (GR) can induce varying conformational changes and biological functions. This study explored the folding pathway of helix 12 (H12) induced by different ligands through molecular dynamics simulations and discovered a novel GR ligand, HP-19, with promising anti-inflammatory activity in the nuclear factor-kappa B signaling pathway and no adverse effects on GR transactivation functions.
Article
Biology
Kubra Akyol, Deryanur Kilic
Summary: This study identified potential selective inhibitors targeting PTP1B through virtual screening and molecular dynamic simulation methods, which may be useful for the treatment of diabetes and cancer.
COMPUTERS IN BIOLOGY AND MEDICINE
(2021)
Article
Oncology
Artem Gridnev, Subhajit Maity, Jyoti R. R. Misra
Summary: The study identified a small molecule inhibitor, JM7, which can indirectly inhibit the activity of YAP by targeting the palmitoylation of TEAD. Inhibiting TEAD palmitoylation destabilizes TEAD and inhibits YAP's oncogenic activity, leading to impaired proliferation and migration of cancer cells.
FRONTIERS IN ONCOLOGY
(2022)
Review
Pharmacology & Pharmacy
F. Potlitz, A. Link, L. Schulig
Summary: Virtual screening approaches, especially AI-assisted deep learning methods, are effective in dealing with ultra-large compound libraries and have shown promise in discovering novel drugs against SARS-CoV-2.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Article
Biochemistry & Molecular Biology
Yue Zhang, Jiankun Song, Yuanzhang Zhou, Huijun Jia, Tianyu Zhou, Yingbo Sun, Qiong Gao, Yue Zhao, Yujie Pan, Zhaolin Sun, Peng Chu
Summary: Ubiquitin-specific protease 22 (USP22) plays a prominent role in tumor development and immune reprogramming, and has been proposed as a potential therapeutic target for cancer. Rottlerin and Morusin were discovered as selective and potent USP22 inhibitors, which can increase histone ubiquitination levels and reduce the expression of Sirt1 and PD-L1 proteins. These findings suggest that Rottlerin and Morusin may have potential as drugs for anticancer therapy.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Haixia Ge, Beihong Ji, Jiahui Fang, Jiayang Wang, Jing Li, Junmei Wang
Summary: In this study, a computational protocol was developed to design/screen novel chemicals that can function as selective CB2 agonists. The protocol successfully identified potent CB2 agonists and antagonists, and their interactions with key residues were analyzed. Three hotspot residues were identified in the loop, which are typically not considered in CB1/CB2 rational ligand design.
ACS CHEMICAL NEUROSCIENCE
(2023)
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)
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, 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
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
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.
Article
Medicine, Research & Experimental
Ioannis Ntanasis-Stathopoulos, Charalampos Filippatos, Maria Gavriatopoulou, Panagiotis Malandrakis, Evangelos Eleutherakis-Papaiakovou, Vassiliki Spiliopoulou, Rodanthi-Eleni Syrigou, Foteini Theodorakakou, Despina Fotiou, Magdalini Migkou, Maria Roussou, Efstathios Kastritis, Meletios Athanasios Dimopoulos, Evangelos Terpos
Summary: Tixagevimab/cilgavimab (Evusheld) appears to be beneficial for high-risk immunocompromised patients with multiple myeloma in preventing COVID-19. Administration of the drug resulted in increased neutralizing-antibody levels and a low incidence of COVID-19, with no new safety concerns emerging.
