Apr 29 2021 12:00 pm
Discovery of Next Generation Microtubule Inhibitors With an Ability to Overcome Multi Drug Resistance
Dr. Rahman Shah Zaib Saleem
Zoom Meetings (Online)
PhD Synopsis defense
Cancer is the second leading cause of death. In 2020, WHO has reported 19.3 million new cases of cancer globally and the cases are expected to increase to around 30.2 million in 2040. Surgery, radiotherapy and chemotherapy are common modes of cancer treatment. In chemotherapy, the use microtubule targeting agent is one of the best strategies to combat this fatal disease because microtubules play a fundamental role in the division of rapidly growing cells. Microtubules are dynamic hollow cylindrical filaments of the cytoskeleton. These are composed of α and β-tubulin. Microtubules are involved in various types of cellular functions to maintain cell shape, intracellular transport, motility, and more importantly in mitotic spindle formation. Thus, these have been targeted through microtubule interacting agents (MTAs) to interfere with the cell cycle, thereby placing cancer cells in chaos leading to mitotic arrest and subsequent cell death. The current MTAs often suffer from development of drug resistance that then aggravates to become multidrug resistance. This prompted us to explore the chemical space and discover next generation of MTAs that could overcome such multidrug resistance. In this regard, we have prepared a novel library of compounds. We have explored its biological activity and mechanism of action. The work has identified a hit that is capable of stabilizing microtubules thus inducing mitotic arrest and subsequent apoptosis. We are now investigating its ability to overcome multidrug resistance. We hope that the compound upon subsequent optimization can be a good lead for the next stages of the drug discovery.