Sulfonylbenzoyl-nitrostyrenes: Potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase

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 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.

Potent Inhibition of Human Telomerase by Nitrostyrene Derivatives

“…␤-bromo-␤-nitrostyrene also acts as an inhibitor of energy transfer in photophosphorylation by binding of the nonphosphorylated (Brandon, 1971). A series of sulfonylbenzoyl nitrostyrene derivatives has shown to be specific inhibitors of the epidermal growth factor receptor tyrosine protein kinase (Traxler et al, 1991). One of these derivatives showed potent antiproliferative effects on mouse epidermal keratinocyte cell line.…”

Covalent Guanosine Mimetic Inhibitors of G12C KRAS

“…For example, squaryldiamides have been studied as diphosphate surrogates in mannosyltransferase targeting sugar-nucleotide mimics; 39 phos- phinylformate has been used as diphosphate isostere in squalene synthetase inhibitors; 41 furthermore, sulfonylbenzoyl-nitrostyrenes were explored as bisubstrate type inhibitors of EGFR, in which the sulfonylbenzoyl moiety served as a diphosphate mimic. 42 However, these bioisosteres suffer from lowered bioactivity when compared with their diphosphate counterparts. We faced this challenge when considering how to generate a cell penetrant version of our prototype G12C KRAS labeling compound SML-8-73-1.…”

The Development of HKI‐272 and Related Compounds for the Treatment of Cancer

“…Basically, these inhibitors were designed to function as bisubstrate inhibitors. Other groups were taking a similar bisubstrate approach [12,13]. In hindsight, this de-novo approach now seems somewhat ambitious although, it yielded inhibitors with IC 50 values in the low lM range for inhibiting the full length EGFR enzyme.…”