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Hypothemycin

Hypothemycin, a resorcylic acid lactone antibiotic, was identified as active in a screen for inhibitors of T cell activation. It was found to inhibit the proliferation of mouse and human T cells stimulated with anti-CD3 mAb + PMA and of human PBMC stimulated with anti-CD3 mAb alone. This inhibition was partially reversed by exogenous IL-2 indicating that it is not due to non-specific toxicity. Hypothemycin potently suppressed the production of IL-2 (IC50: 9 nM) but affected IL-2-induced proliferation to a lesser extent (IC50: 194 nM). Hypothemycin also inhibited IL-6, IL-10, IFN-gamma and TNF-alpha production. By contrast, it markedly enhanced the production of IL-4, IL-5 and IL-13. These effects were seen both at the mRNA and protein secretion levels. Analysis of the effect of hypothemycin on CD69 induction suggested that it disrupts calcineurin-independent rather than calcineurin-dependent signaling. Furthermore, hypothemycin was able to inhibit the phosphorylation of ERK1/2 induced by PMA treatment of T cells. Therefore, hypothemycin represents an inhibitor of T cell activation with a novel mode of action and unique modulatory activity on cytokine production. (source: Immunopharmacology. 1999 Nov;44(3):255-65.).

Current developer:    Merck.

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2: Zhou H, Qiao K, Gao Z, Meehan MJ, Li JW, Zhao X, Dorrestein PC, Vederas JC, Tang Y. Enzymatic synthesis of resorcylic acid lactones by cooperation of fungal iterative polyketide synthases involved in hypothemycin biosynthesis. J Am Chem Soc. 2010 Apr 7;132(13):4530-1. PubMed PMID: 20222707; PubMed Central PMCID: PMC2861853.

3: Fukazawa H, Ikeda Y, Fukuyama M, Suzuki T, Hori H, Okuda T, Uehara Y. The resorcylic acid lactone hypothemycin selectively inhibits the mitogen-activated protein kinase kinase-extracellular signal-regulated kinase pathway in cells. Biol Pharm Bull. 2010 Feb;33(2):168-73. PubMed PMID: 20118535.

4: Dakas PY, Jogireddy R, Valot G, Barluenga S, Winssinger N. Divergent syntheses of resorcylic acid lactones: L-783277, LL-Z1640-2, and hypothemycin. Chemistry. 2009 Nov 2;15(43):11490-7. PubMed PMID: 19821460.

5: Rastelli G, Rosenfeld R, Reid R, Santi DV. Molecular modeling and crystal structure of ERK2-hypothemycin complexes. J Struct Biol. 2008 Oct;164(1):18-23. Epub 2008 May 17. PubMed PMID: 18571434.

6: Reeves CD, Hu Z, Reid R, Kealey JT. Genes for the biosynthesis of the fungal polyketides hypothemycin from Hypomyces subiculosus and radicicol from Pochonia chlamydosporia. Appl Environ Microbiol. 2008 Aug;74(16):5121-9. Epub 2008 Jun 20. PubMed PMID: 18567690; PubMed Central PMCID: PMC2519290.

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9: Hearn BR, Sundermann K, Cannoy J, Santi DV. Semisynthesis and cytotoxicity of hypothemycin analogues. ChemMedChem. 2007 Nov;2(11):1598-600. PubMed PMID: 17691074.

10: Winssinger N, Barluenga S. Chemistry and biology of resorcylic acid lactones. Chem Commun (Camb). 2007 Jan 7;(1):22-36. Epub 2006 Sep 25. Review. PubMed PMID: 17279252.

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14: Isaka M, Suyarnsestakorn C, Tanticharoen M, Kongsaeree P, Thebtaranonth Y. Aigialomycins A-E, new resorcylic macrolides from the marine mangrove fungus Aigialus parvus. J Org Chem. 2002 Mar 8;67(5):1561-6. PubMed PMID: 11871887.

15: Camacho R, Staruch MJ, DaSilva C, Koprak S, Sewell T, Salituro G, Dumont FJ. Hypothemycin inhibits the proliferative response and modulates the production of cytokines during T cell activation. Immunopharmacology. 1999 Nov;44(3):255-65. PubMed PMID: 10598882.

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18: Sonoda H, Omi K, Hojo K, Nishida K, Omura S, Sugita K. Suppression of oncogenic transformation by hypothemycin associated with accelerated cyclin D1 degradation through ubiquitin-proteasome pathway. Life Sci. 1999;65(4):381-94. PubMed PMID: 10421424.