Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase

Yao, Hang‐Ping; Tong, Xiangmin; Wang, Ming-Hai

doi:10.1177/17588359211006957

Cited by 9 publications

(6 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet, as amyloid-targeting drugs are new to the clinic and have much to prove in clinical settings, another class of AD drug is still in need. In this study, we identified another component of the amyloid-beta accumulation cycle, which are the MET signaling complex [19, 28], RAS, EGFR, PLCG and its downstream, the JNK-MAPK signaling. Hence, we propose that the MET complex, RAS, EGFR, PLCG and the JNK-MAPK signaling are new targets to inhibit the amyloid-accumulation cycle and AD intervention drug targets.…”

Section: Discussionmentioning

confidence: 99%

The MET growth signaling complex drives Alzheimer’s Disease-associated brain pathology in aged Shugoshin 1 mouse cohesinopathy model

Rao,

Crane,

Fowler

et al. 2024

Preprint

View full text Add to dashboard Cite

The understanding on molecular processes toward Late-onset Alzheimers Disease (LOAD) has been insufficient to design LOAD intervention drugs. Previously, we discovered transgenic genomic instability model mice Sgo1-/+ accumulate cerebral amyloid-beta in old age. We pro-posed the amyloid-beta accumulation cycle hypothesis, in which cytotoxic, mitogenic and aneuploidgenic amyloid can create an autonomous mitotic cycle leading to accumulation of itself. However, the nature of the growth signaling that drives cells toward pathogenic mitotic cycle remained unidentified. In this study, we hypothesized that the aged Sgo1-/+ mice brains would show signs of mitogenic signaling activation, and searched for growth signaling activated in the vicinity of amyloid-beta, with spatial analysis on the cortex and hippocampus of Sgo1-/+ mice in middle-age and old-age. The analysis indicated activations of kinase signaling p42/44 MAPK ERK1/2, AMPK, JNK, Wnt signaling via GSK3 inactivation, as well as increases of p-TAU and other AD biomarkers, PLCG1, EGFR, MET, Neurofibromin and RAS. Immune activation markers CD45 and CD31 were also elevated in the microenvironment. A majority of activated growth signaling components are of the oncogenic MET signaling complex. The discovery supports re-purposing of cancer drugs targeting the MET signaling complex and EGFR-RAS-MAPK axis for intervention and/or treatment of genomic instability-driven AD.

show abstract

Section: Discussionmentioning

confidence: 99%

The MET growth signaling complex drives Alzheimer’s Disease-associated brain pathology in aged Shugoshin 1 mouse cohesinopathy model

Rao,

Crane,

Fowler

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…MET (which stands for “mesenchymal-epithelial transition” or as an abbreviation for the mutagen N-methylnitrosoguanidine [ 150 ]) is a proto-oncogene and fusion gene discovered in the early 1980s [ 151 ] and found at locus 7q31 on human chromosome 7. It encodes the 170–180 kD, two-chain HGFR (hepatocyte growth factor receptor, or simply c-Met), a protein with transmembrane tyrosine-kinase function [ 152 ], and it is continuously being researched for its involvement in oncologic pathologies, predominantly of the lung and liver but also breast, ovarian, and GI cancers [ 153 ].…”

Section: C-met Inhibitorsmentioning

confidence: 99%

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

Nitulescu,

Stancov,

Seremet

et al. 2023

Molecules

View full text Add to dashboard Cite

The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.

show abstract

“…The dysregulation of the HGF/c-MET axis is closely related to malignant cellular transformation, invasion, and metastasis [ 239 ]. Abnormal MET pathway activation is characterized by MET exon 14-skipping mutations (METex14), MET overexpression, and MET amplification [ 240 ]. MET overexpression can be related to many factors, including the hypoxic environment and transcriptional upregulation of the receptor [ 241 ].…”

Section: Uncommon Mutations Of Nsclcmentioning

confidence: 99%

Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer

Wang

Xing

et al. 2022

Mol Biomed

View full text Add to dashboard Cite

Lung cancer is the leading cause of cancer-related mortality worldwide. The discovery of tyrosine kinase inhibitors effectively targeting EGFR mutations in lung cancer patients in 2004 represented the beginning of the precision medicine era for this refractory disease. This great progress benefits from the identification of driver gene mutations, and after that, conventional and new technologies such as NGS further illustrated part of the complex molecular pathways of NSCLC. More targetable driver gene mutation identification in NSCLC patients greatly promoted the development of targeted therapy and provided great help for patient outcomes including significantly improved survival time and quality of life. Herein, we review the literature and ongoing clinical trials of NSCLC targeted therapy to address the molecular pathways and targeted intervention progress in NSCLC. In addition, the mutations in EGFR gene, ALK rearrangements, and KRAS mutations in the main sections, and the less common molecular alterations in MET, HER2, BRAF, ROS1, RET, and NTRK are discussed. The main resistance mechanisms of each targeted oncogene are highlighted to demonstrate the current dilemma of targeted therapy in NSCLC. Moreover, we discuss potential therapies to overcome the challenges of drug resistance. In this review, we manage to display the current landscape of targetable therapeutic patterns in NSCLC in this era of precision medicine.

show abstract

Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase

Cited by 9 publications

References 116 publications

The MET growth signaling complex drives Alzheimer’s Disease-associated brain pathology in aged Shugoshin 1 mouse cohesinopathy model

The MET growth signaling complex drives Alzheimer’s Disease-associated brain pathology in aged Shugoshin 1 mouse cohesinopathy model

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer

Contact Info

Product

Resources

About