Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)

Lu, Yang; Sun, Haiying

doi:10.1021/acs.jmedchem.0c01248

Cited by 69 publications

(42 citation statements)

References 162 publications

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“…Further, the activation of FAK1 was notable across all time points examined during parasite development, suggesting it may have a continuous role in the infected host cell. These activating phosphorylation event can be mediated by a number of kinases, including the aforementioned Src TK 25 . No implication of FAKs or RET in infection has been reported, but our data suggest it may be of interest to explore this further (Figure 3 and 4).…”

Section: Mappings Analysis Resultsmentioning

confidence: 99%

MAPPINGS v1.0, a tool for network analysis of large phospho-signalling datasets: application to host erythrocyte response to Plasmodium infection

Adderley

O'Donoghue

Davis

et al. 2021

Preprint

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Phosphorylation-based signalling implicates a complex and intertwined series of pathways and is critical to all domains of life. The interconnectivity between pathways results in the emergence of complex networks whose elucidation present a serious challenge. Large datasets of phosphorylation interactions through the activity of kinases on their numerous substrates are constantly being generated, however deciphering the complex network structure hidden in these datasets remains challenging. Many phosphorylation interactions occurring in human cells have been identified and constitute the basis for the known phosphorylation interaction network. We overlayed onto this network phosphorylation datasets obtained from an antibody microarray approach aimed at determining changes in phospho-signalling of host erythrocytes to infection with the malaria parasite Plasmodium falciparum. To analyse the datasets now mapped into the interaction network, we designed a pathway analysis tool denoted MAPPINGS that uses random walks to identify chains of phosphorylation events occurring much more or much less frequently than expected. MAPPINGS highlights pathways of phosphorylation that work synergistically, providing a rapid interpretation of the most critical pathways in each dataset. MAPPINGS confirmed several signalling interactions previously shown to be modulated by infection, and revealed additional interactions which could form the basis of numerous future studies. The MAPPINGS analysis strategy described here is widely applicable to comparative phosphorylation datasets in any context (e.g. response of cells to infection, treatment, or comparison between differentiation stages of any cell populations) and provides a rapid and reliable analysis to guide validation studies.

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Section: Mappings Analysis Resultsmentioning

confidence: 99%

MAPPINGS v1.0, a tool for network analysis of large phospho-signalling datasets: application to host erythrocyte response to Plasmodium infection

Adderley

O'Donoghue

Davis

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Further, the activation of FAK1 was notable across all time points examined during parasite development, suggesting it may have a continuous role in the infected host cell. These activating phosphorylation event can be mediated by a number of kinases, including the aforementioned Src tyrosine kinase 26 . No implication of FAKs or RET in infection has been reported, but our data suggest it may be of interest to explore this further (Figure 3 and 4).…”

Section: Resultsmentioning

confidence: 99%

Network analysis of large phospho-signalling datasets: application to Plasmodium-erythrocyte interactions

Adderley

O'Donoghue

Doerig

et al. 2021

Preprint

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Phosphorylation based signalling is a complicated and intertwined series of pathways critical to all domains of life. This interconnectivity, though essential to life, makes understanding and decoding the interactions difficult. Large datasets of phosphorylation interactions through the activity of kinases on their numerous effectors are now being generated, however interpretation of the network environment remains challenging. In humans, many phosphorylation interactions have been identified across published works to form the known phosphorylation interaction network. We overlayed phosphorylation datasets onto this network which provided information to each of the connections. To analyse the datasets now mapped into a network, we designed a pathway analysis that uses random walks to identify chains of phosphorylation events occurring much more or much less frequently than expected. This analysis highlights pathways of phosphorylation that work synergistically, providing a rapid interpretation of the most critical pathways in a given dataset. Here we used datasets of human red blood cells infected with the notable stages of Plasmodium falciparum asexual development. The analysis identified several known signalling interactions, and additional interactions which could form the basis of numerous future studies. The network analysis designed here is widely applicable to any comparative phosphorylation dataset across infection and disease and can provide a rapid and reliable analysis to guide validation studies.

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“…FAK inhibitors regulate cancer cell angiogenesis, invasion, and migration, and ECs in tumor angiogenesis. Several studies have been conducted to investigate the clinical effect of small-molecule FAK inhibitors ( Chambers et al, 2002 ; Parsons et al, 2008 ; Lu and Sun, 2020 ).…”

Section: Recent Progress Of Protacs Targeting Protein Kinasementioning

confidence: 99%

Targeting Protein Kinases Degradation by PROTACs

Cai

Shao

et al. 2021

Front. Chem.

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Kinase dysregulation is greatly associated with cell proliferation, migration and survival, indicating the importance of kinases as therapeutic targets for anticancer drug development. However, traditional kinase inhibitors binding to catalytic or allosteric sites are associated with significant challenges. The emergence of resistance and targeting difficult-to-degrade and multi-domain proteins are significant limiting factors affecting the efficacy of targeted anticancer drugs. The next-generation treatment approaches seem to have overcome these concerns, and the use of proteolysis targeting chimera (PROTAC) technology is one such method. PROTACs bind to proteins of interest and recruit E3 ligase for degrading the whole target protein via the ubiquitin-proteasome pathway. This review provides a detailed summary of the most recent signs of progress in PROTACs targeting different kinases, primarily focusing on new chemical entities in medicinal chemistry.

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Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)

Cited by 69 publications

References 162 publications

MAPPINGS v1.0, a tool for network analysis of large phospho-signalling datasets: application to host erythrocyte response to Plasmodium infection

MAPPINGS v1.0, a tool for network analysis of large phospho-signalling datasets: application to host erythrocyte response to Plasmodium infection

Network analysis of large phospho-signalling datasets: application to Plasmodium-erythrocyte interactions

Targeting Protein Kinases Degradation by PROTACs

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