Tamoxifen is the most commonly used treatment for patients with ER+ breast cancer (BC). Although many patients benefit from tamoxifen in the adjuvant and metastatic settings, resistance is an important clinical problem. We hypothesized that tamoxifen structure can be modulated to generate a more effective and a better drug-like compound. Over the past three years, extensive structure-activity relationship (SAR) studies were carried out in our laboratories to optimize tamoxifen structure. We generated over 50 tamoxifen analogs and evaluated their activity against MCF-7 (ER+) and the triple negative MDA-MB-231 (ER-, PR-, and HER2 -) human breast cancer cell lines following MTT assay. Both ER+ and triple negative cell lines were used to evaluate if the novel analogs were selectively cytotoxic to the ER+ cells similar to tamoxifen. These studies identified a novel compound GA-11 that non-selectively targeted both the ER+ and triple negative cells, interestingly being more cytotoxic to MDA-MB-231 cells. GA-11 exhibited remarkable activity with IC50 values 7 times lower against MDA-MB-231 (triple negative) and 3 times lower against MCF-7 (ER+) than tamoxifen. GA-11 contains a methoxy group in place of N,N-dimethylethyl functionality of tamoxifen, and an additional polar amine group, which makes it more cytotoxic than tamoxifen to both the cancer cell lines (ER+ and triple negative) while being non-toxic to normal mouse embryonic fibroblast (MEF) cells, suggesting that the cytotoxic response of GA-11 is selective for cancer cells. In addition, GA-11 inhibited the expression of MMP-9, c-Myc and Caveolin, the proteins associated with adhesion, migration and metastasis, in a dose-dependent manner. The response of GA-11 in triple negative MDA-MB-231 cells was more dramatic as compared to MCF-7 (ER+) cells, again suggesting its relative selectivity towards triple negative cells and its potential to target triple-negative breast cancer for which currently no effective chemotherapy options exist. Furthermore, GA-11 inhibited the migration and invasion of MDA-MB-231 cells clearly demonstrating its anti-metastatic properties. In silico evaluation showed that GA-11 with cLogP 4.8 and MW 329, fits better into the requirements of Lipinski's Rule-of-Five, formulated to determine the drug-likeness of a small molecule; than tamoxifen (cLogP 7.34). GA-11 is thus expected to have a better oral bioavailability than tamoxifen. These in vitro studies thus indicate GA-11 to be an effective agent that is superior to tamoxifen both in potency and drug-likeness.

Citation Format: Gurleen Kaur, Mohinder P. Mahajan, Manoj K. Pandey, Parvesh Singh, Srinivasa R. Ramisetti, Arun K. Sharma. A novel tamoxifen analog, GA-11, as potential breast cancer therapeutic. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3067.

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.