Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
USA

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Structure-Based Design of Novel Anticancer Agents

Author(s): F. M. Uckun, E. A. Sudbeck, C. Mao, S. Ghosh, X.-P. Liu, A. O. Vassilev, C. S. Navara, R. K. Narla.

Abstract:

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 b-tubulin and COBRA compounds target a unique binding cavity on a-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 µM. 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.

Keywords: Novel Anticancer Agents, cytoskeletal elements, SPIKET compound, anti-apoptotic function, pleiotropic biologic effects, dibromoquinazoline, immunosuppressive drug, lymphoblastic leukemia, X-linked agammaglobulinemia, tubulin polymerization

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Article Details

VOLUME: 1
ISSUE: 1
Year: 2001
Page: [59 - 71]
Pages: 13
DOI: 10.2174/1568009013334287