Dataset Information

Exploring the chemotherapeutic potential of currently used kinase inhibitors: An update.

ABSTRACT: Protein kinases are enzymes that transfer phosphate to protein, resulting in the modification of the protein. The human genome encodes approximately 538 kinases. Kinases play a role in maintaining a number of cellular processes, including control of the cell cycle, metabolism, survival, and differentiation. Protein kinase dysregulation causes several diseases, and it has been shown that numerous kinases are deregulated in cancer. The oncogenic potential of these kinases is increased by a number of processes, including overexpression, relocation, fusion point mutations, and the disruption of upstream signaling. Understanding of the mechanism or role played by kinases has led to the development of a large number of kinase inhibitors with promising clinical benefits. In this review, we discuss FDA-approved kinase inhibitors and their mechanism, clinical benefits, and side effects, as well as the challenges of overcoming some of their side effects and future prospects for new kinase inhibitor discovery.

SUBMITTER: Naik RR

PROVIDER: S-EPMC9868582 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Exploring the chemotherapeutic potential of currently used kinase inhibitors: An update.

Naik Rajashri R RR Shakya Ashok K AK

Frontiers in pharmacology 20230109

Protein kinases are enzymes that transfer phosphate to protein, resulting in the modification of the protein. The human genome encodes approximately 538 kinases. Kinases play a role in maintaining a number of cellular processes, including control of the cell cycle, metabolism, survival, and differentiation. Protein kinase dysregulation causes several diseases, and it has been shown that numerous kinases are deregulated in cancer. The oncogenic potential of these kinases is increased by a number ...[more]

PMID: 36699049

Similar Datasets

Project description:Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America. Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically. However, it is long before these novel drugs can hit the market, especially due to a scarcity of safety and efficacy data.To reduce the malaria burden, the Medicines for Malaria Venture (MMV) was established in 1999 to develop novel medicines through industry and academic partners' collaboration. However, no reviews were focused following various preclinical and clinical studies published since the MMV initiation (2000) to till date.We identify promising approaches in the global portfolio of antimalarial medicines, and highlight challenges and patient specific concerns of these novel molecules. We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies. Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further, especially for use in pregnant women. Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads. Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy. AQ-13 induced electrocardiac events, which led to prolonged QTc intervals. Tafenoquine, the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency, has raised significant concerns due to its hemolytic activity. Other compounds, including methylene blue (potential transmission blocker) and fosmidomycin (DXP reductoisomerase inhibitor), are available but cannot be used in children.At this stage, we are unable to identify a single magic bullet against malaria. Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission. Newer medicines have also raised concerns in terms of efficacy and safety. Overall, more evidence is needed to effectively reduce the current malaria burden. Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance.

Project description:Sorafenib, lenvatinib and regorafenib, the multi-RTK inhibitors with potent anti-angiogenesis effects, are currently therapeutic drugs generally recommended for the patients with advanced hepatocellular carcinoma (HCC). To date, however, there have been no published studies on the mechanism underling differential effects of the three drugs on HCC cell proliferation, and the proteomic analysis in HCC cell lines treated by regorafenib or lenvatinib. The present study for the first time performed a direct comparison of the cell cycle arrest and apoptosis induction in the Huh-7 cells caused by sorafenib, regorafenib and lenvatinib at respective IC50 using flow cytometry technique, as well as their pharmacological interventions for influencing whole cell proteomics using tandem mass tag-based peptide-labeling coupled with the nLC-HRMS technique. Sorafenib, regorafenib and lenvatinib at respective IC50 drove the remaining surviving Huh-7 cells into a G0/G1 arrest, but lenvatinib and regorafenib were much more effective than sorafenib. Lenvatinib produced a much stronger induction of Huh-7 cells into early apoptosis than sorafenib and regorafenib, while necrotic cell proportion induced by regorafenib was 2.4 times as large as that by lenvatinib. The proteomic study revealed 419 proteins downregulated commonly by the three drugs at respective IC50. KEGG pathway analysis of the downregulated proteins indicated the ranking of top six signaling pathways including the spliceosome, DNA replication, cell cycle, mRNA surveillance, P53 and nucleotide excision repair involved in 33 proteins, all of which were directly related to their pharmacological effects on cell cycle and cell apoptosis. Notably, lenvatinib and regorafenib downregulated the proteins of PCNA, Cyclin B1, BCL-xL, TSP1, BUD31, SF3A1 and Mad2 much more strongly than sorafenib. Moreover, most of the proteins in the P53 signaling pathway were downregulated with lenvatinib and regorafenib by more than 36% at least. In conclusion, lenvatinib and regorafenib have much stronger potency against Huh-7 cell proliferation than sorafenib because of their more potent effects on cell cycle arrest and apoptosis induction. The underling mechanism may be at least due to the 33 downregulated proteins centralizing the signal pathways of cell cycle, p53 and DNA synthesis based on the present proteomics study.

Project description:SARS-CoV-2 (severe acute respiratory syndrome) is highly infectious and causes severe acute respiratory distress syndrome (SARD), immune suppression, and multi-organ failure. For SARS-CoV-2, only supportive treatment options are available, such as oxygen supportive therapy, ventilator support, antibiotics for secondary infections, mineral and fluid treatment, and a significant subset of repurposed effective drugs. Viral targeted inhibitors are the most suitable molecules, such as ACE2 (angiotensin-converting enzyme-2) and RBD (receptor-binding domain) protein-based inhibitors, inhibitors of host proteases, inhibitors of viral proteases 3CLpro (3C-like proteinase) and PLpro (papain-like protease), inhibitors of replicative enzymes, inhibitors of viral attachment of SARS-CoV-2 to the ACE2 receptor and TMPRSS2 (transmembrane serine proteinase 2), inhibitors of HR1 (Heptad Repeat 1)-HR2 (Heptad Repeat 2) interaction at the S2 protein of the coronavirus, etc. Targeting the cathepsin L proteinase, peptide analogues, monoclonal antibodies, and protein chimaeras as RBD inhibitors interferes with the spike protein's ability to fuse to the membrane. Targeting the cathepsin L proteinase, peptide analogues, monoclonal antibodies, and protein chimaeras as RBD inhibitors interferes with the spike protein's ability to fuse to the membrane. Even with the tremendous progress made, creating effective drugs remains difficult. To develop COVID-19 treatment alternatives, clinical studies are examining a variety of therapy categories, including antibodies, antivirals, cell-based therapy, repurposed diagnostic medicines, and more. In this article, we discuss recent clinical updates on SARS-CoV-2 infection, clinical characteristics, diagnosis, immunopathology, the new emergence of variant, SARS-CoV-2, various approaches to drug development and treatment options. The development of therapies has been complicated by the global occurrence of many SARS-CoV-2 mutations. Discussion of this manuscript will provide new insight into drug pathophysiology and drug development.

Dataset Information

Exploring the chemotherapeutic potential of currently used kinase inhibitors: An update.

Publications

Exploring the chemotherapeutic potential of currently used kinase inhibitors: An update.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets