Abstract
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 language | English |
|---|---|
| Pages (from-to) | 1539-1547 |
| Number of pages | 9 |
| Journal | Biochemical Pharmacology |
| Volume | 59 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Jun 2000 |
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Keywords
- EGF receptor kinase
- Enzyme inhibitors
- Fungi
- Oncogene proteins
- Phosphotyrosine
- Protein tyrosine kinase
ASJC Scopus subject areas
- Pharmacology
Cite this
Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin. / Cassinelli, Giuliana; Lanzi, Cinzia; Pensa, Tiziana; Gambetta, Romolo A.; Nasini, Gianluca; Cuccuru, Giuditta; Cassinis, Marco; Pratesi, Graziella; Polizzi, Donatella; Tortoreto, Monica; Zunino, Franco.
In: Biochemical Pharmacology, Vol. 59, No. 12, 06.2000, p. 1539-1547.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin
AU - Cassinelli, Giuliana
AU - Lanzi, Cinzia
AU - Pensa, Tiziana
AU - Gambetta, Romolo A.
AU - Nasini, Gianluca
AU - Cuccuru, Giuditta
AU - Cassinis, Marco
AU - Pratesi, Graziella
AU - Polizzi, Donatella
AU - Tortoreto, Monica
AU - Zunino, Franco
PY - 2000/6
Y1 - 2000/6
N2 - 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.
AB - 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.
KW - EGF receptor kinase
KW - Enzyme inhibitors
KW - Fungi
KW - Oncogene proteins
KW - Phosphotyrosine
KW - Protein tyrosine kinase
UR - http://www.scopus.com/inward/record.url?scp=0034092056&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034092056&partnerID=8YFLogxK
U2 - 10.1016/S0006-2952(00)00278-1
DO - 10.1016/S0006-2952(00)00278-1
M3 - Article
C2 - 10799650
AN - SCOPUS:0034092056
VL - 59
SP - 1539
EP - 1547
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 12
ER -