Computational‐based discovery of FAK FERM domain chemical probes that inhibit HER2‐FAK cancer signaling

Stahl, Erik; Nott, Rohini; Koessel, Karissa; Cance, William G.; Marlowe, Timothy

doi:10.1111/cbdd.13671

Cited by 9 publications

(4 citation statements)

References 37 publications

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“…The results were confirmed by biological assays such as phosphorylation, cellular localization and cellular invasion assays. VS-14 effectively blocked FAK auto-and transphosphorylation, disrupted HER2-FAK co-localization in cells and suppressed HER2-dependent cellular invasion (Stahl et al, 2020). This study identified a new chemical probe in the FAK FERM domain that warrants further investigation for its biological significance in cancer.…”

Section: Design Of Fak Inhibitorsmentioning

confidence: 86%

Focal adhesion kinase—An emerging viable target in cancer and development of focal adhesion kinase inhibitors

Chauhan¹,

Khan

2020

Chem Biol Drug Des

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase located at the extracellular matrix cell adhesion site. This kinase mediates downstream signalling cascades on the cell-extracellular matrix of integrins, cytokine receptors, growth factor receptors and G-protein-coupled receptors. Several studies have suggested the importance of FAK in cancer cell adhesion, motility, proliferation and survival and is over-expressed in cancer cells. There is a growing body of evidence indicating involvement of FAK-mediated signalling and functions in development of tumour cells, making FAK an emerging viable therapeutic target. There is substantial research impetus on development of small molecule FAK inhibitors that impact and inhibit the downstream pathways of FAK, subsequently modulating cancer progression and survival. A variety of scaffolds including hybrid scaffolds have been designed and synthesized with some translating into clinical trials. In addition to the reduction of metastasis and angiogenesis, these inhibitors are effective in inducing tumour cell apoptosis. In this paper, we provide an overview of FAK and analysis of design, synthesis and structure-activity relationship of small molecule FAK inhibitors reported till date. We have discussed FAK inhibitors in clinical trials and highlighted future prospects in the development of FAK inhibitors to augment the armamentarium of cancer therapeutics.

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Section: Design Of Fak Inhibitorsmentioning

confidence: 86%

Focal adhesion kinase—An emerging viable target in cancer and development of focal adhesion kinase inhibitors

Chauhan¹,

Khan

2020

Chem Biol Drug Des

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“…(ii) The allosteric inhibitors of FAK are non-ATP-competitive compounds still undergoing pre-clinical investigation. Allosteric inhibitors have been developed that bind an allosteric site within the kinase domain, but, differently from the ATP-binding site, and seem to be highly specific to FAK [49][50][51][52]. These inhibitors induce an inactive conformation of the kinase domain, hampering interactions with receptor tyrosine kinases (RTKs) or auto-phosphorylation at Tyr397.…”

Section: Fak Inhibitorsmentioning

confidence: 99%

New Insights on the Nuclear Functions and Targeting of FAK in Cancer

Pomella

Cassandri

Braghini

et al. 2022

IJMS

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed and activated in both adult and pediatric cancers, where it plays important roles in the regulation of pathogenesis and progression of the malignant phenotype. FAK exerts its functions in cancer by two different ways: a kinase activity in the cytoplasm, mainly dependent on the integrin signaling, and a scaffolding activity into the nucleus by networking with different gene expression regulators. For this reason, FAK has to be considered a target with high therapeutic values. Indeed, evidence suggests that FAK targeting could be effective, either alone or in combination, with other already available treatments. Here, we propose an overview of the novel insights about FAK’s structure and nuclear functions, with a special focus on the recent findings concerning the roles of this protein in cancer. Additionally, we provide a recent update on FAK inhibitors that are currently in clinical trials for patients with cancer, and discuss the challenge and future directions of drug-based anti-FAK targeted therapies.

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“…The FAK FERM domain serves as a scaffold to mediate protein-protein interaction and links signals from the extracellular compartment to the nucleus [36,37]. For instance, the FERM domain promotes the association of FAK with integrins and activated growth factor receptors and the membrane-cytoskeleton linker ezrin [38][39][40][41]. Recent computational tools have demonstrated that the FERM domain is also involved in the interaction of FAK with HER2 toward the resistance to FAK inhibitors [39].…”

Section: Fak Structural Organization and Activationmentioning

confidence: 99%

“…For instance, the FERM domain promotes the association of FAK with integrins and activated growth factor receptors and the membrane-cytoskeleton linker ezrin [38][39][40][41]. Recent computational tools have demonstrated that the FERM domain is also involved in the interaction of FAK with HER2 toward the resistance to FAK inhibitors [39]. Besides, the FERM domain may facilitate the translocation of FAK into the nuclear compartment, where FAK mediates the regulation of gene expression through the interaction with certain transcription factors and epigenetic modulators [42][43][44][45].…”

Section: Fak Structural Organization and Activationmentioning

confidence: 99%

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

Rigiracciolo

Cirillo

Talia

et al. 2021

Cancers

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Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries have indicated that focal adhesion kinase (FAK), a non-receptor tyrosine kinase, might represent a promising target involved in breast tumorigenesis. Of note, high FAK expression and activity have been tightly correlated with a poor clinical outcome and metastatic features in several tumors, including breast cancer. Recently, a role for the integrin-FAK signaling in mechanotransduction has been suggested and the function of FAK within the breast tumor microenvironment has been ascertained toward tumor angiogenesis and vascular permeability. FAK has been also involved in cancer stem cells (CSCs)-mediated initiation, maintenance and therapeutic responses of breast tumors. In addition, the potential of FAK to elicit breast tumor-promoting effects has been even associated with the capability to modulate immune responses. On the basis of these findings, several agents targeting FAK have been exploited in diverse preclinical tumor models. Here, we recapitulate the multifaceted action exerted by FAK and its prognostic significance in breast cancer. Moreover, we highlight the recent clinical evidence regarding the usefulness of FAK inhibitors in the treatment of breast tumors.

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Computational‐based discovery of FAK FERM domain chemical probes that inhibit HER2‐FAK cancer signaling

Cited by 9 publications

References 37 publications

Focal adhesion kinase—An emerging viable target in cancer and development of focal adhesion kinase inhibitors

Focal adhesion kinase—An emerging viable target in cancer and development of focal adhesion kinase inhibitors

New Insights on the Nuclear Functions and Targeting of FAK in Cancer

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

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