Focal adhesion kinase inhibitors in the treatment of solid tumors: Preclinical and clinical evidence

Quispe, Patricia A.; Lavecchia, Martín J.; León, Ignacio E.

doi:10.1016/j.drudis.2021.11.025

Cited by 24 publications

(17 citation statements)

References 81 publications

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“…Based on this evidence, several clinical studies are evaluating FAK inhibitors in combination with other agents, as reported in Table 1. Indeed, anti-FAK compounds are under clinical study in combination with RTKi, such as the MEK1/2 inhibitors Trametinib and Cobimetinib and the RAF/MEK inhibitor VS-6766 (reviewed in [97]). The combination with the chemotherapeutics Paclitaxel alone or with Carboplatin is under evaluation.…”

Section: Future Directions and Concluding Remarksmentioning

confidence: 99%

“…The combination with the chemotherapeutics Paclitaxel alone or with Carboplatin is under evaluation. Moreover, since nuclear FAK has been shown to remodel chromatin to lead the transcription of pro-inflammatory cytokines, thus contributing to immunoevasion, evaluation of the combination with the immune checkpoint inhibitor Pembrolizumab is also ongoing (reviewed in [97]).…”

Section: Future Directions and Concluding Remarksmentioning

confidence: 99%

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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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Section: Future Directions and Concluding Remarksmentioning

confidence: 99%

Section: Future Directions and Concluding Remarksmentioning

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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“…HRMS calcd for C 21 H 18 ClN 7 O 2 S: 468.1004; found: 468.0999. (12). To a stirred solution of 6-methyl-7H-pyrrolo [2,3d]pyrimidine-2-carbonitrile (800 mg, 4.81 mmol) in DMSO (15 mL) was added NaH (232 mg, 5.80 mmol) at RT.…”

Section: N-[3-({[2-(5-chloro-1h-indol-2-yl)pyrimidin-4-yl]amino}methy...mentioning

confidence: 99%

“…FAK belongs to the family of non-receptor tyrosine kinases and has been associated with different hallmarks of cancer-like cell growth, invasion, and metastasis. − Based on its overexpression and constitutive activation, FAK is considered an attractive therapeutic target in different cancers such as breast, colon, and ovarian, despite lacking any oncogenic alteration. , Six different FAK kinase inhibitors have entered clinical phase I/Ib studies. VS-6063 (also known as defactinib, chemical structure, Supporting Information, Figure S1) is the most advanced and is being tested in several phase II studies as monotherapy and in various combinations. − Suggested combination therapies of defactinib could potentially face challenges due to its limited selectivity for FAK and the potential unpredictable toxicity in combination with other cytotoxic agents. Both diaminopyrimidine PF-431396 (chemical structure, Supporting Information, Figure S1) and defactinib were designed to make use of a specific helical DFG-loop conformation of FAK via a pyridine-linked sulfonamide moiety. , Selectivity investigations, however, challenged this approach (kinase selectivity of defactinib, Supporting Information, Figure S2).…”

Section: Introductionmentioning

confidence: 99%

MSC-1186, a Highly Selective Pan-SRPK Inhibitor Based on an Exceptionally Decorated Benzimidazole-Pyrimidine Core

et al. 2022

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The highly conserved catalytic sites in protein kinases make it difficult to identify ATP competitive inhibitors with kinome-wide selectivity. Serendipitously, during a dedicated fragment campaign for the focal adhesion kinase (FAK), a scaffold that had lost its initial FAK affinity showed remarkable potency and selectivity for serine-arginine-protein kinases 1−3 (SRPK1−3). Non-conserved interactions with the uniquely structured hinge region of the SRPK family were the key drivers of the exclusive selectivity of the discovered fragment hit. Structure-guided medicinal chemistry efforts led to the SRPK inhibitor MSC-1186, which fulfills all hallmarks of a reversible chemical probe, including nanomolar cellular potency and excellent kinome-wide selectivity. The combination of MSC-1186 with CDC2-like kinase (CLK) inhibitors showed additive attenuation of SR-protein phosphorylation compared to the single agents. MSC-1186 and negative control (MSC-5360) are chemical probes available via the Structural Genomics Consortium chemical probe program (https://www.sgc-ffm.uni-frankfurt.de/).

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“…In a biological context, FAK plays a key role in the adhesion, motility, invasion, metastasis, and survival of cancer cells. FAK has been described as a protein that possesses increased tyrosine phosphorylation, which is of particular importance in many carcinomas, including papillary thyroid carcinoma, neck cancer, − malignant melanomas, , bladder cancer, intrahepatic cholangiocarcinoma, ovarian cancer, esophageal cancer, breast cancer, and pancreatic ductal adenocarcinoma. , Additionally, high levels of FAK in cancer patients are generally associated with poor prognosis. Thus, FAK has been considered a promising potential target for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking, Molecular Dynamics Simulations, and Free Energy Calculation Insights into the Binding Mechanism between VS-4718 and Focal Adhesion Kinase

et al. 2022

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Focal adhesion kinase (FAK) is a 125 kDa nonreceptor tyrosine kinase that plays an important role in many carcinomas. Thus, the targeting of FAK by small molecules is considered to be promising for cancer therapy. Some FAK inhibitors have been reported as potential anticancer drugs and have entered into clinical development; for example, VS-4718 is currently undergoing clinical trials. However, the lack of crystal structural data for the binding of VS-4718 with FAK has hindered the optimization of this anticancer agent. In this work, the VS-4718/FAK interaction model was obtained by molecular docking and molecular dynamics simulations. The binding free energies of VS-4718/FAK were also calculated using the molecular mechanics generalized Born surface area method. It was found that the aminopyrimidine group formed hydrogen bonds with the C502 residue of the hinge loop, while the D564 residue of the T-loop interacted with the amide group. In addition, I428, A452, V484, M499, G505, and L553 residues formed hydrophobic interactions with VS-4718. The obtained results therefore provide an improved understanding of the interaction between human FAK and VS-4718. Based on the obtained binding mechanism, 47 novel compounds were designed to target the adenosine 5′-triphosphate-binding pocket of human FAK, and ensemble docking was performed to assess the effects of these modifications on the inhibitor binding affinity. This work is also expected to provide additional insights into potential future target design strategies based on VS-4718.

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Focal adhesion kinase inhibitors in the treatment of solid tumors: Preclinical and clinical evidence

Cited by 24 publications

References 81 publications

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

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

MSC-1186, a Highly Selective Pan-SRPK Inhibitor Based on an Exceptionally Decorated Benzimidazole-Pyrimidine Core

Molecular Docking, Molecular Dynamics Simulations, and Free Energy Calculation Insights into the Binding Mechanism between VS-4718 and Focal Adhesion Kinase

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