The expanding family of c-Met inhibitors in solid tumors: a comparative analysis of their pharmacologic and clinical differences

Fogli, Stefano; Tabbò, Fabrizio; Capuano, Annalisa; Re, Marzia Del; Passiglia, Francesco; Cucchiara, Federico; Scavone, Cristina; Gori, Veronica; Novello, Silvia; Schmidinger, Manuela; Danesi, Romano

doi:10.1016/j.critrevonc.2022.103602

Cited by 6 publications

(4 citation statements)

References 144 publications

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“…Among them, non-selective inhibitors (multi-kinase inhibitors) can simultaneously target multiple tyrosine kinases, which means that the inhibitors can be used as broadspectrum drugs to have therapeutic activity against a variety of cancers. Selective C-MET inhibitors(single enzyme inhibitors) can specifically inhibit specific targets, have higher drug activity, and have the advantage of no off-target effects [8]. Monoclonal antibodies blocking-up the HGF to C-MET and target C-MET, thus inhibitive the HGF-C-MET axis and the C-MET activity.…”

Section: Application Of C-met Inhibitors In Nsclc Treatmentmentioning

confidence: 99%

Application of C-MET Inhibitors in the Treatment of Non-small Cell Lung Cancer

Zhou¹

2022

HSET

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Non-small cell lung cancer (NSCLC) is a kind of refractory lung cancer. Under traditional cisplatin treatment, it is difficult for patients, especially the advanced cancer patients, to have a high cure rate and survival rate. Abnormal histological variants may lead to NSCLC. Mutations in C-MET may lead to abnormal downstream metabolism, which in turn triggers unrestricted cell growth and metastasis. Therefore, C-MET inhibitors can inhibitive the overexpression and activation of C-MET by blocking the gene pathway, in result in that the growth and the spread of cancer cell can be inhibitived. A variety of C-MET inhibitors such as crizotinib, cabonitinib, capmatinib, etc., have been found to have good therapeutic activity and considerable clinical data. This paper discussed the C-MET as a therapeutic target in NSCLC, and outline the applications in clinical and therapeutic effects of various C-MET inhibitors.

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Section: Application Of C-met Inhibitors In Nsclc Treatmentmentioning

confidence: 99%

Application of C-MET Inhibitors in the Treatment of Non-small Cell Lung Cancer

Zhou¹

2022

HSET

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“…Several small molecules have been discovered to inhibit c‐Met along with other kinases, such as selective, dual, or multikinase inhibitors. Crizotinib is an orally available first‐generation ATP competitive drug approved by the FDA, which inhibits the c‐Met signaling pathway 10–11 . Cabozantinib is another FDA‐approved orally bioavailable drug that is used as a multikinase inhibitor against c‐Met, RET, FLT3, KIT, TIE2, VEGFR‐1, and VEGFR‐2 12 .…”

Section: Introductionmentioning

confidence: 99%

“…Crizotinib is an orally available first-generation ATP competitive drug approved by the FDA, which inhibits the c-Met signaling pathway. [10][11] Cabozantinib is another FDA-approved orally bioavailable drug that is used as a multikinase inhibitor against c-Met, RET, FLT3, KIT, TIE2, VEGFR-1, and VEGFR-2. 12 Foretinib or GSK1363089 is an ATP competitive type 2 inhibitor that is primarily used as a dual inhibitor of c-Met and VEGFR-2 in GC.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationship and in silico development of c‐Met kinase inhibitors

Ghosh

Cho

2022

Bulletin Korean Chem Soc

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Overexpression and concomitant drug resistance of c-Met kinase are strongly associated with poor prognosis in gastric carcinoma. This needs the further development of existing lead compounds against c-Met. Herein, we conducted molecular modeling studies of 4-phenoxypyridine derivatives as c-Met kinase inhibitors using docking, molecular dynamics (MD), and binding energy estimation to examine receptor-ligand interaction, complex stability, and binding affinity. We developed statistically significant three-dimensional structureactivity relationship models (3D-QSAR) to correlate the physicochemical characteristics of the inhibitors with their biological activities. The field effects of the chemical descriptors were determined as contour polyhedrons and emphasized as SAR. Thirty new compounds were designed according to the SAR scheme, and their activities were predicted using the 3D-QSAR model. The designed compounds with higher predicted pIC 50 values than the most active compounds in the dataset were subjected to absolute binding free-energy evaluation by free energy perturbation (FEP) method.

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“…Hence, substantial efforts have been devoted to the search for novel anticancer agents to pharmacologically modulate RTK signaling pathways, representing itself in the FDA approval of many inhibitors for clinical management of cancer patients ( Zhao et al, 2021 ). MET receptor is an important oncogenic RTK that has received much attention as a promising drug target in various malignancies ( Fogli et al, 2022 ). This receptor, also named as hepatocyte growth factor receptor (HGFR), is activated by binding to its natural ligand, HGF/scatter factor ( Organ and Tsao, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors

et al. 2022

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The advent of novel receptor tyrosine kinase inhibitors has provided an important therapeutic tool for cancer patients. In this study, a series of quinazolinone hydrazide triazole derivatives were designed and synthesized as novel MET (c-MET) receptor tyrosine kinase inhibitors. The antiproliferative effect of the synthesized compounds was examined against EBC-1, A549, HT-29 and U-87MG cells by MTT assay. MET kinase inhibitory effect was tested by a Homogenous Time Resolved Fluorescence (HTRF) assay. The antiproliferative effect of compounds in a three-dimensional spheroid culture was studied by acid phosphatase (APH) assay, while apoptosis induction was examined by Hoechst 33258 staining. We found that compound CM9 bearing p-bromo benzyl pendant inhibited MET kinase activity at the concentrations of 10–50 μM (% Inhibition = 37.1–66.3%). Compound CM9 showed antiproliferative effect against cancer cells, in particular lung cancer cells with MET amplification (EBC-1) with an IC50 value of 8.6 μM. Moreover, this derivative inhibited cell growth in spheroid cultures in a dose-dependent manner and induced apoptosis in cancer cells. Assessment of inhibitory effect of CM9 against a panel of 18 different protein kinases demonstrated that this compound also inhibits ALK, AXL, FGFR1, FLT1 (VEGFR1) and FLT4 (VEGFR3) more than 50% at 25 μM. Finally, molecular docking and dynamics simulation corroborated the experimental findings and showed critical structural features for the interactions between CM9 and target kinases. The findings of this study present quinazolinone hydrazide triazole derivatives as kinase inhibitors with considerable anticancer effects.

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The expanding family of c-Met inhibitors in solid tumors: a comparative analysis of their pharmacologic and clinical differences

Cited by 6 publications

References 144 publications

Application of C-MET Inhibitors in the Treatment of Non-small Cell Lung Cancer

Application of C-MET Inhibitors in the Treatment of Non-small Cell Lung Cancer

Structure–activity relationship and in silico development of c‐Met kinase inhibitors

Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors

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