Recently identified agents that interact with cytoskeletal elements such as
tubulin include synthetic
spiroketal pyrans (SPIKET) and monotetrahydrofuran compounds (COBRA compounds). SPIKET compounds target the spongistatin binding site of
beta-tubulin and COBRA compounds target a unique binding cavity on
alpha-tubulin. At nanomolar concentrations, the SPIKET compound
SPIKET-P causes
tubulin depolymerization and exhibits potent cytotoxic activity against
cancer cells.
COBRA-1 inhibits
GTP-induced
tubulin polymerization. Treatment of human
breast cancer and
brain tumor cells with
COBRA-1 caused destruction of microtubule organization and apoptosis. Other studies have identified some promising
protein tyrosine kinase inhibitors as anti-
cancer agents. These include EGFR inhibitors such as the
quinazoline derivative
WHI-P97 and the
leflunomide metabolite analog
LFM-A12. Both
LFM-A12 and
WHI-P97 inhibit the in vitro invasiveness of EGFR positive human
breast cancer cells at micromolar concentrations and induce apoptotic cell death. Dimethoxyquinazoline compounds
WHI-P131 and
WHI-P154 inhibit
tyrosine kinase JAK3 in
leukemia cells. Of particular interest is
WHI-P131, which inhibits JAK3 but not JAK1, JAK2, SYK, BTK, LYN, or IRK at concentrations as high as 350 microM. Studies of BTK inhibitors showed that the
leflunomide metabolite analog
LFM-A13 inhibited BTK in
leukemia and
lymphoma cells. Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with
LFM-A13 enhanced their sensitivity to
chemotherapy-induced apoptosis.