Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin.
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 (IC(50) 2.8, 5.5, 81.3, and 128 microM 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(Glu(6)Ala(3)Tyr). 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.
Cassinelli
G
G
Oncologia Sperimentale B, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133, Milan, Italy.
Lanzi
C
C
Pensa
T
T
Gambetta
R A
RA
Nasini
G
G
Cuccuru
G
G
Cassinis
M
M
Pratesi
G
G
Polizzi
D
D
Tortoreto
M
M
Zunino
F
F
D000363:Agaricales / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000494:pharmacology* / Q000627:therapeutic use; D018942:Macrolides / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007783:Lactones; D018942:Macrolides; D011494:Protein Kinases; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases