Tubulin binding compounds that interfere with the dynamic stability of microtubules and disrupt the formation of the mitotic spindle are widely considered one of the most desirable classes of anti-cancer agents. Unfortunately virtually all clinically available tubulin binding agents used for human cancer therapy (paclitaxel, docetaxel, vincristine, vinblastine, etc.) face severe drawbacks, including neurotoxicity, minimal bioavailability and poor solubility, complex synthesis or isolation procedures and, most importantly, the development of drug resistance. Therefore, there exists an urgent need for discovery of novel orally active anti-mitotic compounds that circumvent these liabilities. Employing computer-aided drug design strategies, we have discovered a novel family of 1,3,4-triazole-based small-molecule compounds that target the colchicine binding site of tubulin. A representative subset of five compounds exhibited strong in vitro tubulin polymerization inhibitory activity and cytotoxicity against all parental and multi-drug resistant cancer cell lines tested thus far. These compounds are low molecular weight (<350), easy to synthesize, achiral, and water soluble. The overall goal of this Phase I study is to explore an expanded series of these triazole-based tubulin inhibitors as potential orally active drugs for cancer chemotherapy. To achieve this goal, we will employ an integrated strategy that combines virtual synthesis & screening, structure-based drug design, in silico ADME/Tox filtering, chemical synthesis, and biological characterization of an expanded series of novel triazole-based structural analogs of our existing lead compound T115. Those compounds selected for chemical synthesis will be characterized in vitro in terms of their ability to disrupt the cancer cell cycle and induce cytoskeleton disorganization. We will select 2-5 candidates emanating from our in vitro studies for in vivo efficacy and toxicity studies using mouse models. Snowdon has assembled a capable team with relevant expertise in all aspects of this project to ensure success.
In view of the high rate of death and disability caused by cancer, research aimed at discovering new drugs for cancer treatment is critically important. Based on our existing lead compound T115 which has already demonstrated excellent in vivo activity in a mouse colorectal cancer xenograft model, we will now explore a broader series of triazole-based T115 analogs as antimitotic agents for cancer therapy. Consequently, the proposed study will pursue an integrated discovery program that combines computer-aided design and in silico screening, chemical synthesis, and biological evaluation of a pre-defined series of these T115 analogs. ? ? ?
