Manumycin A

Manumycin A is an antibiotic that acts as a potent and selective farnesyltransferase (FTase) inhibitor with anti-tumor activity.^1,2 It inhibits rat brain FTase with a K_i value of 1.2 µM, thereby preventing Ras activation which requires farnesylation at the C-terminus for membrane attachment.¹ It exhibits significant antitumor activity against K_i-ras-activated solid tumors in mice at a dose of 6.3 mg/kg.¹ Manymycin A inhibits IκB kinase (IKK), independent of FTase inhibition, in an number of cells types with effective concentrations of 2-10 µM.³ In ApoE-deficient mice, Manumycin A treatment for 22 weeks at 5 mg/kg reduced aortic fatty streak lesion size to 43% of vehicle-treated animals, indicating FTase inhibition as a potential target for prevention or treatment of atherosclerosis.⁴

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1. Hara, M., Akasaka, K., Akinaga, S., et al. Identification of Ras farnesyltransferase inhibitors by microbial screening. Proc. Natl. Acad. Sci. USA 90, 2281-2285 (1993).

2. Hara, M., and Han, M. Ras farnesyltransferase inhibitors suppress the phenotype resulting from an activated Ras mutation in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 92, 3333-3337 (1995).

3. Bernier, M., Kwon, Y.K., Pandey, S.K., et al. Binding of manumycin A inhibits I k B kinase ß activity. The Journal of Biological Chemisty 281(5), 2551-2561 (2006).

4. Sugita, M., Sugita, H., and Kaneki, M. Farnesyltransferase inhibitor, manumycin A, prevents atherosclerosis development and reduces oxidative stress in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 27, 1390-1395 (2007).