Structure-based design of novel anticancer agents.
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.
Drug Discovery Program, Parker Hughes Cancer Center, Parker Hughes Institute, 2665 Long Lake Road, St. Paul, Minnesota55113, USA. Fatih_Uckun@ih.org
F M
FM
Uckun
E A
EA
Sudbeck
C
C
Mao
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S
Ghosh
X P
XP
Liu
A O
AO
Vassilev
C S
CS
Navara
R K
RK
Narla
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; C414943:COBRA 1; D005663:Furans; D011714:Pyrans; D011799:Quinazolines; C409002:SPIKET-P; D013141:Spiro Compounds; D014404:Tubulin; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases