Sulfonylbenzoyl-nitrostyrenes: potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase
| Autor: | Johanna Geissler, Peter Traxler, Nicholas B. Lydon, Johannes Roesel, Thomas F. Meyer, Wilhelm Kump, Oskar Wacker, Urs Regenass, Ha L. Bach |
|---|---|
| Rok vydání: | 1991 |
| Předmět: |
Keratinocytes
Models Molecular Chemical Phenomena Stereochemistry Protein tyrosine phosphatase Mitogen-activated protein kinase kinase Benzoates Cell Line Styrenes Mice Drug Discovery Animals Computer Simulation Sulfones Tyrosine Phosphorylation Protein kinase A Protein kinase C Crystallography Epidermal Growth Factor Molecular Structure Chemistry Angiotensin II Autophosphorylation Protein-Tyrosine Kinases Nitro Compounds Enzyme Activation ErbB Receptors Biochemistry Molecular Medicine Cyclin-dependent kinase 9 Tyrosine kinase Cell Division |
| Zdroj: | Journal of medicinal chemistry. 34(8) |
| ISSN: | 0022-2623 |
| Popis: | The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less than or equal to 1 microM. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|