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
Current Cancer Drug Targets
Title: Structure-Based Design of Novel Anticancer Agents
Volume: 1 Issue: 1
Author(s): F. M. Uckun, E. A. Sudbeck, C. Mao, S. Ghosh, X.-P. Liu, A. O. Vassilev, C. S. Navara and R. K. Narla
Affiliation:
Keywords: Novel Anticancer Agents, cytoskeletal elements, SPIKET compound, anti-apoptotic function, pleiotropic biologic effects, dibromoquinazoline, immunosuppressive drug, lymphoblastic leukemia, X-linked agammaglobulinemia, tubulin polymerization
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.
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Uckun M. F., Sudbeck A. E., Mao C., Ghosh S., Liu X.-P., Vassilev O. A., Navara S. C. and Narla K. R., Structure-Based Design of Novel Anticancer Agents, Current Cancer Drug Targets 2001; 1 (1) . https://dx.doi.org/10.2174/1568009013334287
DOI https://dx.doi.org/10.2174/1568009013334287 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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