Abstract A293: Novel allosteric small molecule FAK inhibitors effectively inhibit cancer cell viability and clonogenicity.

Abstract

Abstract Introduction: Focal Adhesion Kinase is overexpressed and activated in many types of tumors and plays an important role in survival. Recently, we developed FAK inhibitor, 1,2,4,5-benzenetetraamine tetrahydrochloride, called Y15, which inhibited FAK autophosphorylation and blocked breast, neuroblastoma, pancreatic, brain and colon cancer tumor growth. Experimental procedures: In this study, eight novel chemical derivatives of Y15, called Y15-I1-I8 were synthesized and tested in a panel of different cancer cell lines. To test the effect on FAK autophosphorylation we performed in vitro ADP-Glo kinase assay with recombinant FAK protein and Western blotting with Y397-FAK antibody. To test the in vivo effect of FAK inhibitors we performed MTT assay, AnnexinV apoptosis and clonogenicity assays in different cancer cell lines. As a control, we used Novartis NVP-TAE-226 FAK inhibitor. Results: By in vitro kinase assay Y15-I1-8 derivatives effectively inhibited FAK autophosphorylation with recombinant purified full length FAK protein. Western blotting demonstrated decreased Y397-FAK and Y418-Src phosphorylation in many cancer cell lines. In addition, these novel FAK inhibitors demonstrated decreased viability, increased apoptosis and inhibition of clonogenicity in lung, melanoma, glioblastoma, pancreatic, breast, and colon cancer cell lines. Some of the novel derivatives were better than parental Y15 inhibitor. Conclusion: Targeting FAK autophosphorylation with novel allosteric derivatives of Y15 is an effective therapy approach. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A293. Citation Format: Vita M. Golubovskaya, Iryna Lebedyeva, Baotran Ho, Michael Yemma, Neha Singh, Makayla Arcara, David Ostrov, Alan Katritzky, William Cance. Novel allosteric small molecule FAK inhibitors effectively inhibit cancer cell viability and clonogenicity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A293.