Abstract 4204: Structure-activity relationship of diphenylamine derivatives to target epithelial to mesenchymal transition in triple negative breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC) is characterized by the loss of hormone receptors and high invasive potential. TNBC cells express high levels of the mesenchymal markers vimentin, fibronectin, N-cadherin, and cadherin11, which are involved in cell invasion and metastasis, and low levels of the epithelial markers E-cadherin, occludins and cytokeratins, which are involved in cellular contact and stability of the cell membrane. Mitogen activated protein kinases, including ERK5 and ERK1/2 are important pro-survival proteins and are known to be upregulated in most cancers. Of these pathways, the MEK5-ERK5 pathway is understudied in triple negative breast cancer, and there are few research tools available to selectively inhibit this pathway. The diphenylamine moiety was derived from the parent molecule Trametinib, a FDA approved MEK1/2 inhibitor for melanoma. Structural modifications were made on the lead molecule to gain selectivity towards MEK. SC-1-151, one of the compounds from this diphenylamine series was identified as a dual MEK1/2 (98.6% inhibition) and MEK5 (59% inhibition) inhibitor. Additionally, we have shown that SC-1-151 attenuates tumor growth in severe combined immunodeficient (SCID) xenograft mice and causes a mesenchymal to epithelial transition (MET) in MDA-MB-231 TNBC cells. The goal of this research is to determine the structural features of diphenylamines that are responsible for MET. E-cadherin and cadherin-11 protein expression and cell morphology were examined to study MET after the treatment of MDA-MB-231 cells with different structural analogs of SC-1-151 for 5 days. Alkyl or N-Methyl piperazine substituents on the amide of ring 1 produced similar result as SC-1-151, and substituting the amide group with acid or ester also induced MET. In contrast, ortho-fluoro, para-iodo functional groups of the arene ring 2, when replaced with a meta-bromo substituent did not induce MET. Therefore, our data suggest the necessary functional groups for inducing MET include the hydrogen atom on the amine linkage, and the iodine atom on the arene ring 2. Future studies will be performed to determine the specific protein interactions of the promising compounds. Citation Format: Akshita B. Bhatt, Thomas D. Wright, Katie Anna, Mohit Gupta, Patrick Flaherty, Van Hoang, Matthew Burow, Jane E. Cavanaugh. Structure-activity relationship of diphenylamine derivatives to target epithelial to mesenchymal transition in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4204.