Synthesis and Biological Evaluation of Small Molecular Drug Candidates for the Treatment of Her2 Overexpressed Breast Cancer
Date of Award
Doctor of Philosophy in Clinical-Bioanalytical Chemistry
In the US breast cancer is the most common cancer after skin cancer. Currently in the US the average risk of a woman to develop breast cancer in her life is roughly 12%. About 25-30% of breast cancer patients have HER2 overexpressed tumor, and the growth of tumor cell is depend on HER2 pathway. It has been well-documented that patients with over-expressed HER2 are associated with increased disease recurrence, worse prognosis and lower survival. Currently there are two type of HER2 targeting drug. The first group is HER2 monoclonal antibody drugs such as trastuzumab approved by FDA in 1998; the second type is intracellular tyrosine kinase inhibitors such as lapatinib approved by FDA in 2007. Presently trastuzumab is one of the most efficient in clinic for HER2 over-expressed breast cancer patients, however many patients didn’t gain benefit due to the de novo or acquire resistance. The resistance of trastuzumab involves multiple cellular pathway, research indicates that HSP27 participate in the development of resistance. There are studies indicate that HER2 is one of the client proteins of HSP27. HER2 would be downregulated via inhibition of HSP27. Previously, a lead compound JCC76 which generated from COX-2 inhibitor Nimesulide was found to target HSP27. Herein, 23 analogs of JCC76 were synthesized. Cell viability assay was used for screen the analogs that selectively inhibit HER2 overexpressed cell proliferation. Western-blot and chaperone assay were used to investigate the anti-proliferate cellular mechanism. The selected compounds, 16 and 17, inhibited the protective function of small chaperone. In the HER2 downregulation experiment, the results indicate a dose-dependent downregulation of HER2 for both compounds. In the second study we try to improve the druggable characteristics of the compounds by reducing the compound size and molecular weight. Totally 60 compounds were synthesized and screen for cell growth inhibitory ability against variance cell line, 5 compounds with potent proliferate inhibitory activity were identified. The SAR study indicates several compounds with 3-trifluoromethylbenzamide groups showed potent and selective inhibition of HER2 overexpressed breast cancer cells.
Zhao, Anran, "Synthesis and Biological Evaluation of Small Molecular Drug Candidates for the Treatment of Her2 Overexpressed Breast Cancer" (2018). ETD Archive. 1058.