Structure-Based Design of Novel Anticancer Agents

Authors: Uckun F.M.; Sudbeck E.A.; Mao C.; Ghosh S.; Liu X.-P.; Vassilev A.O.; Navara C.S.; Narla R.K.

Source: Current Cancer Drug Targets, Volume 1, Number 1, May 2001 , pp. 59-71(13)

Publisher: Bentham Science Publishers

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 ?M. 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

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1568009013334287

Publication date: 2001-05-01

• Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes, genes.
  Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in cancer.
  As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.

• In this: publication
• By this: publisher
• In this Subject: Oncology ,  Pharmacology
• By this author: Uckun F.M. ;  Sudbeck E.A. ;  Mao C. ;  Ghosh S. ;  Liu X.-P. ;  Vassilev A.O. ;  Navara C.S. ;  Narla R.K.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers