The significance of microtubules as a molecular target for chemotherapeutic treatments has been known for decades. Tubulin, which makes up microtubules binds numerous small molecule ligands, which result in the alteration of microtubule dynamics leading to cell cycle arrest and cell death. Some of these ligands are currently used clinically for the treatment of several types of cancer and include the drugs paclitaxel and vinblastine. These drugs bind to several distinct binding sites within beta tubulin, which have been identified through electron crystallography. The drawback of these drugs is their indiscriminate binding to all cells leading to the death of both cancerous and healthy cells. Hence despite the overall success of the vinca alkaloid and taxane drug families side effects such as neurodegradation seriously impair the prognosis for many cancer patients treated with them. Moreover, in many cases drug resistance develops in the course of chemotherapy. We have focused on computational searches, optimization and testing new and re-purposing old molecules that interfere with the formation of mitotic spindles during cell division in tumors. To build the molecular models of our target tubulin, we used the program Modeller that uses alignment of the sequences with known related structures to obtain spatial restraints that the output structure must satisfy. Missing regions are predicted by simulated annealing of a molecular mechanics model. The existence and distribution of various tubulin isoforms is the basis for novel chemotherapeutic drug design that can differentiate between different cell types to reduce side effects. The quality of the resulting models for tubulin isoforms was investigated by an analysis of ten human beta tubulin isoforms regarding their differences within ligand binding sites. New promising colchicine derivatives have been designed and computationally tested for isoform specificity. The stabilities of these derivatives have been computationally evaluated using quantum mechanical methods. They have been synthesized and tested in vitro and in vivo. Testing of these compounds on a panel of tumour cell cultures has produced promising results for their ability to selectively target specific cancer cells. Mitotic abnormalities, such as an impaired spindle were also observed in the treated cells and almost all the cells were blocked in prometaphase. The cytotoxicity of the colchicine derivatives was further quantitated by utilizing clonogenic assays. We have also determined that the colchicine derivatives control the migration of vascular endothelial cells for additional therapeutic benefits. We have shown that a class of novel colchicine derivatives: (a) can inhibit migration in primary endothelial cells, (b) can selectively induce cytotoxicity in rapidly dividing cells, (c) in mouse models can cause anti-angiogenic effects. We will also report the results of in vivo studies of our lead compound in patient-derived xenograft mouse tests for efficacy in metastatic bladder cancer and in healthy rats for toxicity. The lead compound, CR42-24, is currently completing pre-clinical studies and is expected to be submitted for IND approval by FDA in a year.