Sulfonylbenzoyl-nitrostyrenes: potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase.
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.
Traxler
P M
PM
Oncology and Virology Research Department, Ciba-Geigy Ltd., Basel, Switzerland.
Wacker
O
O
Bach
H L
HL
Geissler
J F
JF
Kump
W
W
Meyer
T
T
Regenass
U
U
Roesel
J L
JL
Lydon
N
N
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D003198:Computer Simulation; D003461:Crystallography; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009574:Nitro Compounds / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013343:Styrenes / Q000737:chemistry / Q000494:pharmacology*; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*
D001565:Benzoates; D009574:Nitro Compounds; D013343:Styrenes; D013450:Sulfones; D000804:Angiotensin II; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases