Abstract
Structural optimization of a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl compounds, potential new irreversible EGFR inhibitors, was performed to improve pharmacokinetic properties of the compounds. This led to compound 2v with improved aqueous solubility and good pharmacokinetic properties which at the nanomolar level potently inhibits gefitinib-resistant EGFR(L858R/T790M) kinase and displays strong antiproliferative activity against H1975 nonsmall cell lung cancer cells. The new inhibitor also shows promising antitumor efficacy in a murine EGFR(L858R/T790M)-driven H1975 xenograft model without effect on body weight. These studies provide new lead compounds for further development of drugs for treatment of gefitinib-resistant nonsmall cell lung cancer patients.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Dose-Response Relationship, Drug
-
Drug Design*
-
ErbB Receptors / antagonists & inhibitors*
-
Heterocyclic Compounds, 2-Ring / chemical synthesis
-
Heterocyclic Compounds, 2-Ring / chemistry
-
Heterocyclic Compounds, 2-Ring / pharmacology*
-
Humans
-
Male
-
Mice
-
Mice, SCID
-
Molecular Structure
-
Pyrimidines / chemical synthesis
-
Pyrimidines / chemistry
-
Pyrimidines / pharmacology*
-
Rats
-
Rats, Sprague-Dawley
-
Solubility
-
Structure-Activity Relationship
-
Thermodynamics
-
Xenograft Model Antitumor Assays
Substances
-
1-(1-acryloylpyrrolidin-3-yl)-7-(3-methyl-4-(4-methylpiperazin-1-yl)phenylamino)-3-phenyl-3,4-dihydropyrimido(4,5-d)pyrimidin-2(1H)-one
-
Antineoplastic Agents
-
Heterocyclic Compounds, 2-Ring
-
Pyrimidines
-
ErbB Receptors