AbstractsMedical & Health Science

Preclinical evaluation and identification of potent tubulin and Hsp27 inhibitors as anticancer agents

by Rati Lama

Institution: Cleveland State University
Department: College of Sciences and Health Professions
Degree: PhD
Year: 2015
Keywords: Chemistry; tubulin; Hsp27; tumor spheroid; a-crystallin; chaperone
Record ID: 2061669
Full text PDF: http://rave.ohiolink.edu/etdc/view?acc_num=csu1430232901


Increased rates of failure and high costs are serious challenges in cancer drug discovery. These challenges are attributed to the inability in selection of drugs with acceptable toxicity and efficacy profiles in early drug developmental stages and to the cytotoxic side effects and development of resistance of current chemotherapeutic agents. There is a need to select and identify anticancer drug candidates with novel biological targets and strong pharmacological activities against cancer in preclinical stages through reliable in vitro methods prior to in vivo screening. Therefore this study focuses on the evaluation of anticancer agents that target tubulin and Hsp27 in various cancer disease models and the identification of most potent candidates. Non-steroidal anti-inflammatory drugs (NSAIDs) have been extensively studied for their anti-tumorigenic activity. Nimesulide [N-(4-nitro-2-phenoxyphenyl) methane sulfonamide], a NSAID and a COX-2 inhibitor was used as a lead compound to generate more potent analogs. Compared to Nimesulide, the new analogs showed better activities in cell proliferation studies. Through proteomic approaches a second-generation active compound CSUOH0901 was found to target tubulin and Hsp27. Tubulin and Hsp27 are critical for cancer cell growth and proliferation and serve as novel targets for anticancer drug discovery. Nimesulide third generation compound libraries were screened in various breast cancer cell lines and the most potent analogs were identified. Eight representative compounds from Nimesulide first, second and third generation compound libraries were selected and evaluated for their Hsp27 chaperone and tubulin polymerization inhibitory activities. Further to better predict the in vivo efficacy of the anticancer candidates, an easy-handling and cost-effective 3D spheroid model suitable for small molecule anticancer compounds screening was developed using NSCLC H292 cells. The representative compounds identified as tubulin and Hsp27 binders were screened in 2D, 3D and in vivo models and the most potent candidates were identified. The results revealed structural moieties important for Hsp27 and tubulin inhibition and further defined the structure activity relationship between tubulin and Hsp27 effects of the compounds. Overall, this approach of preclinical screening highlighted an accurate strategy to eliminate poor candidates and identify the most promising analogs at early stages of anticancer drug development.