400 FAK Inhibitor VS-4718 Attenuates Breast Cancer Stem Cell Function and Inhibits Tumor Growth in Vivo

Xu, Qiong; Kolev, Vihren N.; Vidal, Chantal; Shapiro, IM; Ring, JE; Padval, Mahesh V.; Keegan, Mitchell; Pachter, Jonathan A.

doi:10.1016/s0959-8049(12)72198-6

Cited by 3 publications

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“…Additionally, a window-of-opportunity study to assess tumor biomarker responses to VS-6063 is being conducted in patients undergoing s u r g e r y f o r m a l i g n a n t p l e u r a l m e s o t h e l i o m a (ClinicalTrials.gov, NCT02004028). FAK inhibition has also been shown to reduce the viability of cancer stem cells in merlin-deficient models of breast cancer [35], suggesting that the utility of merlin loss as a potential biomarker for FAK inhibitory activity should be further evaluated in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors

et al. 2015

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Section: Discussionmentioning

confidence: 99%

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors

et al. 2015

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“…VS‐4718 inhibits FAK phosphorylation at Y397 in cellular assays with an IC 50 in the 100 nM range, and it also reduces the proportion of cancer stem cells in Aldefluor and Hoechst dye exclusion assays with an IC 50 value of approximately 100 nM . Another work has shown that malignant pleural mesothelioma (MPM) cell lines with mutated NF2 have IC 50 values in the 100 nM range, while MPM cell lines with wild‐type NF2 have IC 50 values greater than 1 μM .…”

Section: Discussionmentioning

confidence: 99%

Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program

Kurmasheva

Görlick

Kolb

et al. 2016

Pediatr Blood Cancer

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VS-4718 was tested against the PPTP’s in vitro cell line panel and showed a median relative IC50 of 1.22 µM. VS-4718 was tested in vivo against the PPTP xenograft models using a dose of 50 mg/kg administered by the oral route twice daily for 21 days. VS-4718 induced significant differences in EFS distribution compared to control in 18 of 36 of the evaluable solid tumor xenografts and in 0 of 8 acute lymphoblastic leukemia (ALL) xenografts, but no xenograft lines showed tumor regression. Future plans include further evaluating the role of FAK inhibition in combination with ABL kinase inhibitors for Ph-positive ALL.

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“…The VS-4718 has also demonstrated a cellular IC 50 of ∼100 nM in malignant pleural mesothelioma cell lines and breast carcinoma. Furthermore, it has a median relative cellular IC 50 of 1.22 μM against the pediatric preclinical testing program cell line. − These results indicate that VS-4718 possesses on-target and off-target concentrations of <100 nM and >1.0 μM, respectively, in these cell lines . In terms of its clinical development, VS-4718 has been demonstrated to act as a potential inhibitor for triple-negative breast cancer stem cells .…”

Section: Introductionmentioning

confidence: 92%

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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400 FAK Inhibitor VS-4718 Attenuates Breast Cancer Stem Cell Function and Inhibits Tumor Growth in Vivo

Cited by 3 publications

References 0 publications

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors

Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program

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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