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

Targeting of deregulated protein tyrosine kinases has been proposed as a ne w approach in the therapeutic intervention against pathological processes i ncluding proliferative disorders and cancer. Using a screening approach bas ed on a comparative evaluation of antiproliferative effects in a panel of t umor 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 derivative s of these products, diacetyl-CA anal dimethyl-CA, were identified as inhib itors of protein tyrosine kinases. Naturally occurring CA, CB, and CD showe d inhibitory activity in kinase assays against the Ret/ptc1 and epidermal g rowth 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 mu M respectively, for the most potent compound CD). CB was shown to be a non-competitive inhibitor of EGF-R with respect t o 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. Fur ther, 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 wh en administered daily (ip) to mice bearing ascitic A431 tumor. These findin gs indicate that clavilactones represent the prototypes of a new structural class of tyrosine kinase inhibitors deserving further investigation. BIOCH EM PHARMACOL. (C) 2000 Elsevier Science Inc.