EGFR erbB1 Inhibitor
     
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EGFR erbB1 Inhibitor

4-Hydroxy-3-methoxynitrostyrene

Potent inhibitor of EGF-R with IC50 = 7.9 ?M and showed antiproliferative activity with IC50 values of 3.5 ?M.

nw-egfr_inhibitor12

OTAVAchemicals Catalogue Number:   0107930017

CAS Registry Number:  6178-42-3

Purity: 99%

Ref.: Trader et al. Sulfonylbenzoyl-Nitrostyrenes: Potential Bisubstrate Type Inhibitors of the EGF-Receptor Tyrosine Protein Kinase . Journal  of  Medicinal Chemistry, (1991), Vol.  34, No. 8. 2328-2337.

Abstract: 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  51  microM.  No inhibition of  the v-ab1  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 y-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.

 
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