Abstract
Microtubule inhibitors, as chemotherapeutic drugs, are widely used for cancer treatment in clinic. However, the development of multidrug resistance (MDR) in cancer is a major challenge for microtubule inhibitors in its clinical implementation. From a high throughput drug screening using cells transformed by oncogenic RAS, we identified a small molecule AR8-1006 that blocks cell proliferation. The analysis of structure-activity relationship indicated that this serial of scaffold represents a potent inhibitor of tumor cell growth. AR8-1006 shows activities against a larger panel of more than 1000 human cancer cell lines with a wide variety of tissue origins. Further analysis showed that this compound depolymerizes microtubules and affects formation of the spindle. Interestingly, it induces the spike-like conformation of microtubules in vitro and in vivo, which is different from typical microtubule modulators. Structural analysis revealed that this serial of compounds binds to the colchicine pocket at the intra-dimer interface, though mostly not overlapping with colchicine binding. More importantly, AR8-1006 displays favorable pharmacological properties on overcoming tumor MDR both in vitro and in vivo. Taken together, our data reveal a novel scaffold represented by AR8-1006 that could be developed as cancer therapeutics, especially for tumor multidrug resistance.
