jm0600390_si_001.pdf (6.18 MB)
The Combi-Targeting Concept: Synthesis of Stable Nitrosoureas Designed to Inhibit the Epidermal Growth Factor Receptor (EGFR)
journal contribution
posted on 2006-06-15, 00:00 authored by Juozas Domarkas, Fabienne Dudouit, Christopher Williams, Qiu Qiyu, Ranjita Banerjee, Fouad Brahimi, Bertrand Jacques Jean-ClaudeAccording to the “combi-targeting” concept, the EGFR tyrosine kinase (TK) inhibitory potency of compounds
termed “combi-molecules” is critical for selective growth inhibition of tumor cells with disordered expression
of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory
potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and
ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their
EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the
ureido or the nitrosoureido moiety of the synthesized drugs. Compounds (3‘-Cl and Br series) with small
angles (0.5−3°) were generally stronger EGFR TK inhibitors than those with large angles (18−21°). This
was further corroborated by ligand−receptor van der Waals interaction calculations that showed significant
binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative
studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the
erbB2 oncogene, showed that IC50 values for inhibition of EGFR TK could be good predictors of their
selective potency against the serum-stimulated growth of the erbB2-tranfected cell line (Pearson r = 0.8).
On the basis of stability (t1/2), EGFR TK inhibitory potency (IC50), and selective erbB2 targeting, compound
23, a stable nitrosourea, was considered to have the structural requirements for further development.