Design, synthesis, and biological evaluation of novel FAK scaffold inhibitors targeting the FAK-VEGFR3 protein-protein interaction.
Focal adhesion kinase (FAK) and vascular endothelial growth factor receptor 3 (VEGFR3) are tyrosine kinases, which function as key modulators of survival and metastasis signals in cancer cells. Previously, we reported that small molecule chlorpyramine hydrochloride (C4) specifically targets the interaction between FAK and VEGFR3 and exhibits anti-tumor efficacy. In this study, we designed and synthesized a series of 1 (C4) analogs on the basis of structure activity relationship and molecular modeling. The resulting new compounds were evaluated for their binding to the FAT domain of FAK and anti-cancer activity. Amongst all tested analogs, compound 29 augmented anti-proliferative activity in multiple cancer cell lines with stronger binding to the FAT domain of FAK and disrupted the FAK-VEGFR3 interaction. In conclusion, we hope that this work will contribute to further studies of more potent and selective FAK-VEGFR3 protein-protein interaction inhibitors.
Department of Cell Stress Biology/PDT Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Priyanka N
PN
Gogate
Department of Cell Stress Biology/PDT Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Manivannan
M
Ethirajan
Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.|CureFAKtor Pharmaceuticals, Orchard Park, NY 14127, USA.
Elena V
EV
Kurenova
Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Andrew T
AT
Magis
Department of Cell Stress Biology/PDT Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Ravindra K
RK
Pandey
Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.|CureFAKtor Pharmaceuticals, Orchard Park, NY 14127, USA.
William G
WG
Cance
D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D005029:Ethylenediamines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
D005029:Ethylenediamines; D047428:Protein Kinase Inhibitors; C004664:chloropyramine; D040321:Vascular Endothelial Growth Factor Receptor-3; D051416:Focal Adhesion Protein-Tyrosine Kinases
FAK scaffold inhibitor; Focal adhesion kinase; Focal adhesion targeting domain; Protein–protein interaction; Vascular endothelial growth factor receptor-3