Chemosensitizing anti-cancer activity of LFM-A13, a leflunomide metabolite analog targeting polo-like kinases.
LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide) has recently been identified as an inhibitor of Polo-like kinases (Plk). LFM-A13 does not inhibit other serine/threonine kinases including CDK, CHK, RAF, DAPK, IKK, IRAK, JNK, MAPK, PKC and SAPK. LFM-A13-treated human cancer cells develop abnormal mitotic spindles and G(2)/M-arrest during cell cycle progression. LFM-A13 was not toxic to rodents or dogs at daily dose levels as high as 100 mg/kg. Notably, at a low dose level of 10 mg/kg, which does not result in delayed tumor progression in the MMTV/neu transgenic mouse model of HER2 positive breast cancer, LFM-A13 markedly enhanced the anti-cancer activity of the mitotic spindle poison paclitaxel. These results indicate that LFM-A13 may be useful in the treatment of cancer patients.
Uckun
Fatih M
FM
Parker Hughes Cancer Center, 2848 Patton Road, Roseville, Minnesota 55113, USA. fatih_uckun@ih.org
D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017239:Paclitaxel / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D008941:Spindle Apparatus / Q000187:drug effects; D025521:Tumor Suppressor Proteins; D000097868:Polo-like Kinases
D000577:Amides; D000970:Antineoplastic Agents; D009570:Nitriles; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C118451:LFM A13; C486256:PLK3 protein, human; D000097868:Polo-like Kinases