Chemical Dissection of the Cell Cycle for Anticancer Drug Discovery and Target Identification
- Author(s): Lo, Yu-Chen
- Advisor(s): Torres, Jorge
- Teitell, Michael A
- et al.
The cell cycle is governed by highly regulated mechanisms that mandate organism’s proliferation and survival. On the other hand, malignant human diseases like cancer often arise by uncontrolled cell cycle progression. The cell cycle of mammalian cells can be easily perturbed by chemical compounds (drugs), leading to check point activation, cell cycle arrests and eventual apoptosis (cell death). Consequently, identifying critical cell cycle targets whose bioactivities can be modulated by small molecules present a promising strategy to advance our understanding and treatment of neoplasm disease. Here, we present a new approach to dissect mammalian cell cycles using small molecule cell cycle screen to identify diverse hit compounds with potent anticancer activities. In particular, we identified MI-181, a potent tubulin destabilizing agent that is active against multiple cancer cell lines. Further structure study indicates that it binds to a distinct site close to the colchicines binding pocket. As an alternative, we further applied cell cycle analysis to repurpose anticancer agents from non-cancer drugs and have identified six FDA compounds with novel cytotoxic properties. To enable large-scale profiling of cell cycle targets, we developed a new computational approach for target identification called “CSNAP” based on network algorithm and consensus statistics. CSNAP analysis of M-phase inhibitors identified three novel mitotic targets not previous associated with mitosis and one novel mitotic inhibitor interacting with the colchicine site of beta tubulin. To improve target predictability and identify scaffold hoppers, we considered ligand 3D conformation in an improved CSNAP3D program. CSNAP3D analysis of M-phase compounds discovered low molecular weight taxol mimetics that bound to the taxane site, stabilized microtubule formation, and demonstrated promising transport properties.