Introduction: The bacterial topoisomerases DNA gyrase and topoisomerase IV are validated targets for development of novel antibacterial agents. Fluoroquinolones inhibit the catalytic GyrA and/or ParC(GrlA) subunit and have been commonly used, although these have toxicity liabilities that restrict their use. The ATPase GyrB and ParE(GrlB) subunits have been much less explored and after withdrawal of novobiocin, there are no further marketed inhibitors . ATP-competitive inhibitors of GyrB and/or ParE(GrlB) are of special interest, as this target has been validated, and it is expected that many of the problems associated with fluoroquinolones can be avoided.
Areas Covered: This review summarises the development of ATP-competitive inhibitors of GyrB and/or ParE(GrlB) as novel antibacterial agents over the last 10 years. Structural features of the new inhibitors and their optimisation strategies are highlighted.
Expert Opinion: The development of novel ATP-competitive inhibitors of GyrB and/or ParE(GrlB) is ongoing in industrial and academical research. Development of resistance is one of the most problematic issues, but GyrB/ParE(GrlB) inhibitors do not show cross-resistance with fluoroquinolones. Other common issues, such as low solubility, high protein binding, development of off-target resistance, are related to the structures of the inhibitors themselves, which is thus a main focus of design strategies. With some now in early clinical development, there is reasonable expectation that novel ATP-competitive inhibitors of GyrB/ParE(GrlB) will reach the market in the near future.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1080/13543776.2019.1575362 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Chemoproteomic Profiling of for Characterization of Anti-fungal Kinase Inhibitors.
bioRxiv
January 2025
Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
is a growing health concern as the leading causal agent of systemic candidiasis, a life-threatening fungal infection with a mortality rate of ~40% despite best available therapy. Yck2, a fungal casein kinase 1 (CK1) family member, is the cellular target of inhibitors YK-I-02 (YK) and MN-I-157 (MN). Here, multiplexed inhibitor beads paired with mass spectrometry (MIB/MS) employing ATP-competitive kinase inhibitors were used to define the selectivity of these Yck2 inhibitors across the global proteome.
View Article and Find Full Text PDFInteraction of Heat Shock Protein 90 (HSP90), Ganetespib, and 5-Fluorouracil by Computational Approach for Colorectal Cancer Therapy.
Crit Rev Oncog
January 2025
Department of Biotechnology, Dr. B.R. Ambedkar University, Srikakulam 532410, Andhra Pradesh, India.
The heat shock protein 90 kDa (HSP90) is highly conserved across diverse species, including humans, and upregulated in various cancers. As a result, it has been identified as a promising target for advancing anticancer medicine. The introduction of combinatorial chemistry in drug discovery has emphasized the need to develop new technologies in screening, designing, decoding, synthesizing, and screening combinatorial drug libraries.
View Article and Find Full Text PDFTargeting mTOR Kinase with Natural Compounds: Potent ATP-Competitive Inhibition Through Enhanced Binding Mechanisms.
Pharmaceuticals (Basel)
December 2024
Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait.
: The mammalian target of the rapamycin (mTOR) signaling pathway is a central regulator of cell growth, proliferation, metabolism, and survival. Dysregulation of mTOR signaling contributes to many human diseases, including cancer, diabetes, and obesity. Therefore, inhibitors against mTOR's catalytic kinase domain (KD) have been developed and have shown significant antitumor activities, making it a promising therapeutic target.
View Article and Find Full Text PDFStructure-based design of new anticancer N3-Substituted quinazolin-4-ones as type I ATP-competitive inhibitors targeting the deep hydrophobic pocket of EGFR.
Comput Biol Med
January 2025
Drug Design and Discovery Lab, Helmy Institute of Medical Sciences, Zewail City of Science, Technology and Innovation, Giza, 12578, Egypt; Biomedical Sciences Program, University of Science and Technology, Zewail City of Science, Technology and Innovation, Giza, 12578, Egypt. Electronic address:
Epidermal growth factor receptor (EGFR) is amongst the earliest targeted kinases by small-molecule inhibitors for the management of EGFR-positive cancer types. While a few inhibitors are granted FDA approval for clinical use, discovery of new inhibitors is still of merit to enhance ligand-binding stability and subsequent enzyme inhibition. Thus, a structure-based design approach was adopted to devise a new series of twenty-nine N3-substituted quinazolin-4-ones as type I ATP-competitive inhibitors targeting the deep hydrophobic pocket of EGFR.
View Article and Find Full Text PDFFrom challenges to solutions: A review of fourth-generation EGFR tyrosine kinase inhibitors to overcome the C797S triple mutation in non-small cell lung cancer.
Eur J Med Chem
February 2025
Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, 425405, India. Electronic address:
This Review discusses recent advancements in the development of fourth-generation "Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs)" targeting resistance mutations, with an emphasis on the C797S mutation in "Non-small Cell Lung Cancer (NSCLC)". While first, second, and third-generation EGFR-TKIs have made significant progress in overcoming EGFR kinase resistance, the emergence of the EGFR-C797S mutation poses a substantial challenge, particularly in the context of resistance to Osimertinib. Fourth-generation TKIs are classified into ATP-competitive, allosteric, and ortho-allosteric inhibitors, with the goal of enhancing specificity for mutant EGFR while minimizing off-target effects on wild-type EGFR to reduce toxicity.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!