Discovery of a Novel <i>Fusarium Graminearum</i> Mitogen-Activated Protein Kinase (FgGpmk1) Inhibitor for the Treatment of Fusarium Head Blight

Fu, Weitao; Wang, Ercheng; Ke, Di; Yang, Hao; Chen, Lingfeng; Shao, Jingjing; Hu, Xueping; Xu, Lei; Liu, Na; Hou, Tingjun

doi:10.1021/acs.jmedchem.1c01227

Cited by 7 publications

(4 citation statements)

References 48 publications

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“…The optimal predicted binding mode of the ternary complex was then subjected to conventional molecular dynamics (MD) simulations. The 200 ns MD simulation protocol was similar to that previously reported . The calculation of RMSDs and extraction of representative structures of the simulated ternary complex was performed using the CPPTRAJ module in Amber 20 package .…”

Section: Methodsmentioning

confidence: 99%

Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

Luo

et al. 2023

J. Med. Chem.

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Abnormal activation of fibroblast growth factor receptors (FGFRs) results in the development and progression of human cancers. FGFR2 is frequently amplified or mutated in cancers; therefore, it is an attractive target for tumor therapy. Despite the development of several pan-FGFR inhibitors, their long-term therapeutic efficacy is hindered by acquired mutations and low isoform selectivity. Herein, we report the discovery of an efficient and selective FGFR2 proteolysis-targeting chimeric molecule, LC-MB12, that incorporates an essential rigid linker. LC-MB12 preferentially internalizes and degrades membrane-bound FGFR2 among the four FGFR isoforms; this may promote greater clinical benefits. LC-MB12 exhibits superior potency in FGFR signaling suppression and anti-proliferative activity compared to the parental inhibitor. Furthermore, LC-MB12 is orally bioavailable and shows significant antitumor effects in FGFR2-dependent gastric cancer in vivo. Taken together, LC-MB12 is a candidate FGFR2 degrader for alternative FGFR2-targeting strategies and offers a promising starting point for drug development.

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Section: Methodsmentioning

confidence: 99%

Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

Luo

et al. 2023

J. Med. Chem.

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“…Molecular docking is one of the most commonly used methods in structure-based drug design, which can predict the affinity between the ligand and the target; so, it can be used to screen bioactive compounds in the early stage of drug development. , Therefore, we chose BRAF inhibitor as an example to verify our mode. First, the crystal structure of the BRAF complex (PDB ID: 3OG7 and 6XFP ) was downloaded from the PDB database for simple optimization, including adding hydrogen atoms, distributing protonation state of residues, and minimizing the energy with the OPLS-2005 force field .…”

Section: Materials and Methodsmentioning

confidence: 99%

Transformer-Based Generative Model Accelerating the Development of Novel BRAF Inhibitors

et al. 2021

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The de novo drug design based on SMILES format is a typical sequence-processing problem. Previous methods based on recurrent neural network (RNN) exhibit limitation in capturing long-range dependency, resulting in a high invalid percentage in generated molecules. Recent studies have shown the potential of Transformer architecture to increase the capacity of handling sequence data. In this work, the encoder module in the Transformer is used to build a generative model. First, we train a Transformer-encoder-based generative model to learn the grammatical rules of known drug molecules and a predictive model to predict the activity of the molecules. Subsequently, transfer learning and reinforcement learning were used to fine-tune and optimize the generative model, respectively, to design new molecules with desirable activity. Compared with previous RNN-based methods, our method has improved the percentage of generating chemically valid molecules (from 95.6 to 98.2%), the structural diversity of the generated molecules, and the feasibility of molecular synthesis. The pipeline is validated by designing inhibitors against the human BRAF protein. Molecular docking and binding mode analysis showed that our method can generate small molecules with higher activity than those carrying ligands in the crystal structure and have similar interaction sites with these ligands, which can provide new ideas and suggestions for pharmaceutical chemists.

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“…This study provides ideas for the discovery of antifungals for Fusarium head blight management. 37 The role of MAPKs in being antifungal targets is so extensive that some potential fungicidal active substances have been reported. As is shown in Table 1, Liang et al suggested that the MAPK named PGPBS in Pyrenophora graminea, a phytopathogenic fungus, has pivotal roles in various biological processes, and its resistance to iprodione and tebuconazole has also been studied.…”

Section: Application Of Protein Kinases In Resistingmentioning

confidence: 99%

“…As is shown in Table , the EC 50 value of reported Compound 94 is 3.46 μg·mL –1 , and this compound may control the phosphorylation of FgGpmk1 and affect the nuclear localization of downriver FgSte12. This study provides ideas for the discovery of antifungals for Fusarium head blight management …”

Section: Protein Kinases As Potential Targets For Antifungalsmentioning

confidence: 99%

Protein Kinases as Potential Targets Contribute to the Development of Agrochemicals

Sun

Wang

Gao

et al. 2023

J. Agric. Food Chem.

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Using agrochemicals against pest insects, fungi, and weeds plays a major part in maintaining and improving crop yields, which helps to solve the issue of food security. Due to the limited targets and resistance of agrochemicals, protein kinases are regarded as attractive potential targets to develop new agrochemicals. Recently, a lot of investigations have shown the extension of agrochemicals by targeting protein kinases, implying an increasing concern for this kind of method. However, few people have summarized and discussed the targetability of protein kinases contributing to the development of agrochemicals. In this work, we introduce the research on protein kinases as potential targets used in crop protection and discuss the prospects of protein kinases in the field of agrochemical development. This study may not only provide guidance for the contribution of protein kinases to the development of agrochemicals but also help nonprofessionals such as students learn and understand the role of protein kinases quickly.

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Discovery of a Novel Fusarium Graminearum Mitogen-Activated Protein Kinase (FgGpmk1) Inhibitor for the Treatment of Fusarium Head Blight

Cited by 7 publications

References 48 publications

Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

Transformer-Based Generative Model Accelerating the Development of Novel BRAF Inhibitors

Protein Kinases as Potential Targets Contribute to the Development of Agrochemicals

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