Hypothemycin

Hypothemycin is a resorcylic acid lactone polyketide originally isolated from H. tricothecoides that has diverse biological activities.^1,2,3,4,5,6 Hypothemycin inhibits MEK (IC₅₀ = 15 nM) and other protein kinases containing a conserved cysteine residue in the ATP-binding domain, including ERK, PDGFR, VEGFR, PKD1, and MAPKAP5/MK5.^3,4 It also inhibits transforming growth factor β-activated kinase 1 (TAK1) in vitro (IC₅₀ = 33 nM).⁵ Hypothemycin inhibits proliferation of cancer cell lines dependent on activating mutations, including A549, MV-4-11, and EOL1 cells (IC₅₀s = 6, 0.006, and 0.0004 µM, respectively) and reduces tumor growth in Ma44 and HCT116 mouse xenograft models when administered at a dose of 25 mg/kg per day.^4,6

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1. Agatsuma, T., Takahashi, A., Kabuto, C., et al. Revised structure and stereochemistry of hypothemycin. Chem. Pharm. Bull. 41(2), 373-375 (1993).

2. Xu, L., Xue, J., Wu, P., et al. Antifungal activity of hypothemycin against Peronophythora litchii in vitro and in vivo. J. Agric. Food Chem. 61(42), 10091-10095 (2013).

3. Zhao, A., Lee, S.H., Mojena, M., et al. Resorcylic acid lactones: Naturally occurring potent and selective inhibitors of MEK. J. Antibiot. (Tokyo) 52(12), 1086-1094 (1999).

4. Schirmer, A., Kennedy, J., Murli, S., et al. Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides. Proc. Natl. Acad. Sci. USA 103(11), 4234-4239 (2006).

5. Fakhouri, L., El-Elimat, T., Hurst, D.P., et al. Isolation, semisynthesis, covalent docking and transforming growth factor beta-activated kinase 1 (TAK1)-inhibitory activities of (5Z)-7-oxozeaenol analogues. Bioorg. Med. Chem. 23(21), 6993-6999 (2015).

6. Tanaka, H., Nishida, K., Sugita, K., et al. Antitumor efficacy of hypothemycin, a new Ras-signaling inhibitor. Jpn. J. Cancer Res. 90(10), 1139-1145 (1999).