The Development of FAK Inhibitors: A Five-Year Update

Spallarossa, Andrea; Tasso, Bruno; Russo, Eleonora; Villa, Carla; Brullo, Chiara

doi:10.3390/ijms23126381

Cited by 33 publications

(14 citation statements)

References 72 publications

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“…FAK is a key kinase involved in the formation of cell adhesive plaque. The downregulation of FAK expression can lead to changes in a wide range of signal-regulated proteins that are related to tumor invasion and migration, such as the downregulation of MMP-9 activity in the extracellular matrix, PI3K/Akt/NF-κB signal pathway inhibition, and F-actin depolymerization ( 73 ). In conclusion, the above-mentioned studies reveal that TQ can inhibit several key molecules such as FAK, Akt, NF-κB, and MMP-9 and that these molecules interact in a cascade to affect the metastasis of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Advances in research on the relationship between thymoquinone and pancreatic cancer

Zhao

Liu

et al. 2023

Front. Oncol.

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Pancreatic cancer has one of the worst prognoses among the most common cancers in the world. Its characteristics include a high rate of metastasis and chemotherapeutic resistance, which present major challenges to the medical community. The potential anticancer effects of thymoquinone (TQ), which is the main bioactive compound of the black seeds of the Nigella sativa plant, have recently received widespread attention for their potential use in treating pancreatic cancer. TQ can inhibit cell proliferation, promote cancer cell apoptosis, inhibit cell invasion and metastasis, enhance chemotherapeutic sensitivity, inhibit angiogenesis, and exert anti-inflammatory effects. These anticancer effects predominantly involve the nuclear factor (NF)-κB, phosphoinositide 3 kinase (PI3K)/Akt, Notch, transforming growth factor (TGF)-β, c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways as well as the regulation of the cell cycle, matrix metallopeptidase (MMP)-9 expression, and pyruvate kinase isozyme type M2 (PKM2) activity. TQ regulates the occurrence and development of pancreatic cancer at multiple levels and through multiple targets that communicate with each other. In this review, we summarize and discuss the analogs and carriers of TQ that have been developed in recent years. Given its multilevel anticancer effects, TQ may become a new therapeutic drug for treating pancreatic cancer in the future. This review presents a brief introduction to the research that has been conducted on TQ in relation to pancreatic cancer to provide a theoretical basis for future studies on the topic.

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Section: Discussionmentioning

confidence: 99%

Advances in research on the relationship between thymoquinone and pancreatic cancer

Zhao

Liu

et al. 2023

Front. Oncol.

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“…Furthermore, inhibiting FAK kinase activity has been reported to reduce cancer stem cells and attract regulatory T cells (Tregs), resulting in changes to the tumor immune microenvironment and increasing sensitivity to chemotherapy. 6,7 Several inhibitors, such as Defactinib , 8 VS-4718 , 9 CEP-3744 , 10 and PF-562271 , 11 as shown in Fig. 1, are currently being developed to control cancer growth.…”

Section: Introductionmentioning

confidence: 99%

Computational investigation of novel pyrimidine derivatives as potent FAK inhibitorsvia3D-QSAR, molecular docking, molecular dynamics simulation and retrosynthesis

El Bahi,

Boutalaka,

El Alaouy

et al. 2023

New J. Chem.

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“…ATP-competitive inhibitors targeting the kinase domain are promising therapeutic interventions for several types of cancers, and many are currently being studied in advanced clinical trials. However, throughout the lead optimization process, there was an uncertain dilemma between selectivity and efficacy, demanding more collaborative efforts using computational modeling and medicinal chemistry [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional-QSAR and Relative Binding Affinity Estimation of Focal Adhesion Kinase Inhibitors

Ghosh

Cho

2023

Molecules

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Precise binding affinity predictions are essential for structure-based drug discovery (SBDD). Focal adhesion kinase (FAK) is a member of the tyrosine kinase protein family and is overexpressed in a variety of human malignancies. Inhibition of FAK using small molecules is a promising therapeutic option for several types of cancer. Here, we conducted computational modeling of FAK-targeting inhibitors using three-dimensional structure–activity relationship (3D-QSAR), molecular dynamics (MD), and hybrid topology-based free energy perturbation (FEP) methods. The structure–activity relationship (SAR) studies between the physicochemical descriptors and inhibitory activities of the chemical compounds were performed with reasonable statistical accuracy using CoMFA and CoMSIA. These are two well-known 3D-QSAR methods based on the principle of supervised machine learning (ML). Essential information regarding residue-specific binding interactions was determined using MD and MM-PB/GBSA methods. Finally, physics-based relative binding free energy (∆∆GRBFEA→B) terms of analogous ligands were estimated using alchemical FEP simulation. An acceptable agreement was observed between the experimental and computed relative binding free energies. Overall, the results suggested that using ML and physics-based hybrid approaches could be useful in synergy for the rational optimization of accessible lead compounds with similar scaffolds targeting the FAK receptor.

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The Development of FAK Inhibitors: A Five-Year Update

Cited by 33 publications

References 72 publications

Advances in research on the relationship between thymoquinone and pancreatic cancer

Advances in research on the relationship between thymoquinone and pancreatic cancer

Computational investigation of novel pyrimidine derivatives as potent FAK inhibitorsvia3D-QSAR, molecular docking, molecular dynamics simulation and retrosynthesis

Three-Dimensional-QSAR and Relative Binding Affinity Estimation of Focal Adhesion Kinase Inhibitors

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