1233953-80-4Relevant articles and documents
6-Aryl and heterocycle quinazoline derivatives as potent EGFR inhibitors with improved activity toward gefitinib-sensitive and -resistant tumor cell lines
Hamed, Mostafa M.,AbouElElla, Dalal A.,Keeton, Adam B.,Piazza, Gary A.,Abadi, Ashraf H.,Hartmann, Rolf W.,Engel, Matthias
, p. 1495 - 1504 (2013)
A group of novel anilinoquinazoline derivatives with variable aryl and heterocyclic substituents at position6 were synthesized and tested for their EGFR-inhibitory activity. Aryl and heterocyclic rings were attached to the quinazoline scaffold through different linkages such as imine, amide, and thiourea. Most of the aryl and heterocyclic derivatives showed potent inhibition of wild-type EGFR with IC50 values in the low nanomolar range. Among these, thiourea derivatives 6a, 6b and compound 10b also retained significant activity toward the gefitinib-insensitive EGFRT790M/L858R mutant, displaying up to 24-fold greater potency than gefitinib. In addition, cell growth inhibitory activity was tested against cancer cell lines with wild-type (KB cells) and mutant EGFR (H1975 cells). Several compounds including 6a were found to be more potent than the reference compound gefitinib toward both cell lines, as was the case for compound 10b against H1975 cells. Therefore, compounds 6a and 10b in particular may serve as new leads for the development of inhibitors effective against wild-type EGFR as well as gefitinib-resistant mutants.
Irreversible inhibition of epidermal growth factor receptor activity by 3-aminopropanamides
Carmi, Caterina,Galvani, Elena,Vacondio, Federica,Rivara, Silvia,Lodola, Alessio,Russo, Simonetta,Aiello, Stefania,Bordi, Fabrizio,Costantino, Gabriele,Cavazzoni, Andrea,Alfieri, Roberta R.,Ardizzoni, Andrea,Petronini, Pier Giorgio,Mor, Marco
, p. 2251 - 2264 (2012/05/20)
Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3- carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6- yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.
