Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin

Giuliana Cassinelli, Cinzia Lanzi, Tiziana Pensa, Romolo A. Gambetta, Gianluca Nasini, Giuditta Cuccuru, Marco Cassinis, Graziella Pratesi, Donatella Polizzi, Monica Tortoreto, Franco Zunino

Research output: Contribution to journalArticlepeer-review


Targeting of deregulated protein tyrosine kinases has been proposed as a new approach in the therapeutic intervention against pathological processes including proliferative disorders and cancer. Using a screening approach based on a comparative evaluation of antiproliferative effects in a panel of tumor cells with differential expression of protein tyrosine kinases, three benzoquinoid macrolidic fungal metabolites produced by Clitocybe clavipes, clavilactones A, B, and D (CA, CB, and CD) and two semisynthetic derivatives of these products, diacetyl-CA and dimethyl-CA, were identified as inhibitors of protein tyrosine kinases. Naturally occurring CA, CB, and CD showed inhibitory activity in kinase assays against the Ret/ptc1 and epidermal growth factor receptor (EGF-R) tyrosine kinases, while being less effective against the v-Abl tyrosine kinase and p34(cdc2) serine/threonine kinase (IC50 2.8, 5.5, 81.3, and 128 μM respectively, for the most potent compound CD). CB was shown to be a non-competitive inhibitor of EGF-R with respect to ATP or poly(Glu6Ala3Tyr). CD also preferentially inhibited the growth of A431 cells, which overexpress a constitutively active EGF-R, as opposed to IGROV-1 and SKOV-3 cells, which express low levels of the receptor. Further, EGF-R was shown to be a target for clavilactones in A431 cells, since EGF-induced receptor autophosphorylation was inhibited in the presence of CB, CD, and diacetyl-CA. Both CD and diacetyl-CA displayed weak activity when administered daily (i.p.) to mice bearing ascitic A431 tumor. These findings indicate that clavilactones represent the prototypes of a new structural class of tyrosine kinase inhibitors deserving further investigation. Copyright (C) 2000 Elsevier Science Inc.

Original languageEnglish
Pages (from-to)1539-1547
Number of pages9
JournalBiochemical Pharmacology
Issue number12
Publication statusPublished - Jun 2000


  • EGF receptor kinase
  • Enzyme inhibitors
  • Fungi
  • Oncogene proteins
  • Phosphotyrosine
  • Protein tyrosine kinase

ASJC Scopus subject areas

  • Pharmacology


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