The combi-targeting concept: synthesis of stable nitrosoureas designed to inhibit the epidermal growth factor receptor (EGFR).
According 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 degrees ) were generally stronger EGFR TK inhibitors than those with large angles (18-21 degrees ). 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 IC(50) 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 (t(1/2)), EGFR TK inhibitory potency (IC(50)), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.
Domarkas
Juozas
J
Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/ Royal Victoria Hospital, Montreal, H3A1A1, Quebec, Canada.
Dudouit
Fabienne
F
Williams
Christopher
C
Qiyu
Qiu
Q
Banerjee
Ranjita
R
Brahimi
Fouad
F
Jean-Claude
Bertrand Jacques
BJ
D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D041681:NIH 3T3 Cells; D009607:Nitrosourea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014162:Transfection
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D005038:Ethylnitrosourea; D008024:Ligands; D009607:Nitrosourea Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; C512073:1-(2-chloroethyl)-1-nitroso-3-methyl-3-((4-(3-chlorophenyl)amino)quinazolin-6-yl)urea