Chemosensitizing anti-cancer activity of LFM-A13, a leflunomide metabolite analog targeting polo-like kinases.

Abstract

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.

• Authors: Fatih M Uckun
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 6 Issue 24 Pg. 3021-6 (Dec 15 2007) ISSN: 1551-4005 [Electronic] United States
• PMID: 18073537 (Publication Type: Journal Article)

Chemical References

• Amides
• Antineoplastic Agents
• LFM A13
• Nitriles
• Tumor Suppressor Proteins
• PLK3 protein, human
• Protein Serine-Threonine Kinases
• Paclitaxel

Topics

• Amides (pharmacology, therapeutic use, toxicity)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use, toxicity)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Dogs
• Female
• Humans
• Male
• Mammary Neoplasms, Experimental (drug therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Nitriles (pharmacology, therapeutic use, toxicity)
• Paclitaxel (therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Spindle Apparatus (drug effects)
• Tumor Suppressor Proteins