Design, synthesis, and biological evaluation of novel FAK scaffold inhibitors targeting the FAK–VEGFR3 protein–protein interaction

Gogate, Priyanka N.; Ethirajan, Manivannan; Kurenova, Elena; Magis, Andrew T.; Pandey, Ravindra K.; Cance, William G.

doi:10.1016/j.ejmech.2014.04.041

Cited by 28 publications

(18 citation statements)

References 39 publications

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“…Compound C10 (previously compound 29) was synthesized and its purity was evaluated as previously described [16]. …”

Section: Methodsmentioning

confidence: 99%

“…DMSO or C10 were added at the indicated concentrations for 72 h and cell viability was measured as previously described [16]. …”

Section: Methodsmentioning

confidence: 99%

“…Cells were seeded at a density such that they were approximately 80% confluent after 24 h. Compound C10 was added at the indicated concentrations and cells were incubated at 37°C for 24 h. Total cell lysates were prepared as previously described [16]. …”

Section: Methodsmentioning

confidence: 99%

“…We recently developed a novel FAK scaffold inhibitor, C10 (previously compound 29) that disrupted the FAK-VEGFR3 interaction and showed a dramatic increase in potency and binding affinity to the FAT domain of FAK attributed mainly due to its proximity to the tyrosine 925 site in the FAT domain of FAK [16]. FAK-Y925 can be phosphorylated by Src, which in turn creates a docking site for the SH2 domain containing adaptor protein, Grb2 that further activates the Ras/ MAPK pathway [33].…”

Section: Introductionmentioning

confidence: 99%

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Targeting the C-terminal focal adhesion kinase scaffold in pancreatic cancer

et al. 2014

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Preliminary studies in our laboratory have demonstrated the importance of both the NH2 and COOH terminus scaffolding functions of focal adhesion kinase (FAK). Here, we describe a new small molecule inhibitor, C10 that targets the FAK C-terminus scaffold. C10 showed marked selectivity for cells overexpressing VEGFR3 when tested in isogenic cell lines, MCF7 and MCF7-VEGFR3. C10 preferentially inhibited pancreatic tumor growth in vivo in cells with high FAK-Y925 and VEGFR3 expression. Treatment with C10 led to a significant inhibition in endothelial cell proliferation and tumor endothelial and lymphatic vessel density and decrease in interstitial fluid pressure. These results highlight the underlying importance of targeting the FAK scaffold to treat human cancers.

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“…Compound C10 (previously compound 29) was synthesized and its purity was evaluated as previously described [16]. …”

Section: Methodsmentioning

confidence: 99%

“…DMSO or C10 were added at the indicated concentrations for 72 h and cell viability was measured as previously described [16]. …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting the C-terminal focal adhesion kinase scaffold in pancreatic cancer

et al. 2014

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“…B-and T-cell immunostimulatory molecules [247] -though surprisingly, no epitope-based vaccines have yet been adopted in clinical practice, [248] as well as anti-inflammatory agents, [249] anti-cancer drugs, [250] and cell-penetrating peptides [251] with both cytotoxic and drug delivery potential. [252] Once identified, synthesis of peptides typically occurs using a recombinant (biological) production platform or a chemical synthesis approach.…”

Section: Progress Reportmentioning

confidence: 99%

Adding Functions to Biomaterial Surfaces through Protein Incorporation

et al. 2016

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The concept of biomaterials has evolved from one of inert mechanical supports with a long-term, biologically inactive role in the body into complex matrices that exhibit selective cell binding, promote proliferation and matrix production, and may ultimately become replaced by newly generated tissues in vivo. Functionalization of material surfaces with biomolecules is critical to their ability to evade immunorecognition, interact productively with surrounding tissues and extracellular matrix, and avoid bacterial colonization. Antibody molecules and their derived fragments are commonly immobilized on materials to mediate coating with specific cell types in fields such as stent endothelialization and drug delivery. The incorporation of growth factors into biomaterials has found application in promoting and accelerating bone formation in osteogenerative and related applications. Peptides and extracellular matrix proteins can impart biomolecule- and cell-specificities to materials while antimicrobial peptides have found roles in preventing biofilm formation on devices and implants. In this progress report, we detail developments in the use of diverse proteins and peptides to modify the surfaces of hard biomaterials in vivo and in vitro. Chemical approaches to immobilizing active biomolecules are presented, as well as platform technologies for isolation or generation of natural or synthetic molecules suitable for biomaterial functionalization.

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Vascular‐targeted low dose photodynamic therapy stabilizes tumor vessels by modulating pericyte contractility

Cavin¹,

Riedel²,

Rosskopfova³

et al. 2019

Lasers Surg Med

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Vascular‐targeted low‐dose photodynamic therapy (L‐PDT) was shown to improve chemotherapy distribution in malignant pleural tumors such as malignant pleural mesothelioma (MPM). However, the mechanisms triggered by L‐PDT on the tumor vasculature are still debated. In pericyte and endothelial cell co‐cultures, we show that pericytes exhibit enhanced sensitivity towards L‐PDT compared to endothelial cells, displaying actin stress fibers and cellular contraction via Rho/ROCK kinase signaling myosin light chain and focal adhesion kinase phosphorylation (MLC‐P, FAK‐P). We then confirm, in two separate MPM models, in mice the phosphorylation of the MLC in pericytes specifically following L‐PDT. Furthermore, while L‐PDT does not affect tumor vascular density or diameter, we show that it enhances tumor vascular pericyte coverage, leads to a drop in tumor interstitial fluid pressure and enhances the transport of FITC‐dextran throughout tumors. In conclusion, L‐PDT has the potential to stabilize the tumor vascular bed which improves vascular transport. The mechanism described in the present study may help translate and optimize this approach in patients. Lasers Surg. Med. 51:550–561, 2019. © 2019 Wiley Periodicals, Inc.

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Design, synthesis, and biological evaluation of novel FAK scaffold inhibitors targeting the FAK–VEGFR3 protein–protein interaction

Cited by 28 publications

References 39 publications

Targeting the C-terminal focal adhesion kinase scaffold in pancreatic cancer

Targeting the C-terminal focal adhesion kinase scaffold in pancreatic cancer

Adding Functions to Biomaterial Surfaces through Protein Incorporation

Vascular‐targeted low dose photodynamic therapy stabilizes tumor vessels by modulating pericyte contractility

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