Agents that either promote or inhibit
tubulin polymerization exhibit anticancer activity by disrupting normal mitotic spindle assembly and cell division as well as inducing apoptosis. Recently identified novel agents that target
tubulin include synthetic
spiroketal pyrans (SPIKET), targeting the spongistatin binding site of
beta-tubulin, and COBRA compounds, targeting a unique binding cavity on
alpha-tubulin. At nanomolar concentrations, the SPIKET compound
SPIKET-P caused
tubulin depolymerization in cell-free turbidity assays and exhibited potent cytotoxic activity against
cancer cells as evidenced by destruction of microtubule organization, and prevention of mitotic spindle formation in human
breast cancer cells. Molecular modeling studies predicted a high-affinity interaction of the first COBRA compounds, COBRA-0 and
COBRA-1, with a unique hydrophobic binding site on
alpha-tubulin located between the
GTP/
GDP binding site and the M-loop. Further studies showed that
COBRA-1 inhibited
GTP-induced
tubulin polymerization in cell-free
tubulin turbidity assays. Treatment of human
breast cancer and
brain tumor (
glioblastoma) cells with
COBRA-1 caused destruction of microtubule organization and apoptosis.
COBRA-1 activated the pro-apoptotic
c-Jun N-terminal kinase (JNK) signal transduction pathway. COBRA and SPIKET compounds represent two new classes of
tubulin targeting agents that show promise as anticancer drugs.