Development of erlotinib derivatives as CIP2A-ablating agents independent of EGFR activity
Journal
Bioorganic and Medicinal Chemistry
Journal Volume
20
Journal Issue
20
Pages
6144-6153
Date Issued
2012
Author(s)
Kuen-Feng Chen
Abstract
Cancerous inhibitor of PP2A (CIP2A) is a novel human oncoprotein that inhibits PP2A, contributing to tumor aggressiveness in various cancers. Several studies have shown that downregulation of CIP2A by small molecules reduces PP2A-dependent phosphorylation of Akt and induces cell death. Here, a series of mono- and di-substituted quinazoline and pyrimidine derivatives based on the skeleton of erlotinib (an EGFR inhibitor) were synthesized and their bioactivities against hepatocellular carcinoma were evaluated. The di-substituted quinazoline and pyrimidine derivatives were more potent inhibitors of cancer-cell proliferation than the mono-substituted derivatives. In particular, compound 1 with chloride at position 2 of quinazoline was as potent as erlotinib in inducing cell death but no inhibition for EGFR activity. Further assays confirmed a correlation between cell death, and CIP2A and Akt inhibition by these derivatives. Among all the derivatives, compounds 19 and 22 showed the most potent antiproliferative activities and the strongest inhibition of CIP2A and p-Akt expression. ? 2012 Elsevier Ltd. All rights reserved.
Subjects
CIP2A; Erlotinib; HCC; Pyrimidine; Quinazoline
SDGs
Other Subjects
2 chloro 6,7 dimethoxy n (4 phenoxyphenyl)quinazolin 4 amine; 2 chloro n (2 fluoro 5 methylophenyl) 6,7 dimethoxyquinazolin 4 amine; 2 chloro n (3 chlorophenyl) 6,7 dimethoxyquinazolin 4 amine; 2 chloro n (3 chlorophenyl)pyrimidin 4 amine; 2 chloro n (3 ethynylphenyl) 6,7 dimethoxy n methylquinazolin 4 amine; 2 chloro n (3 ethynylphenyl) 6,7 dimethoxyquinazolin 4 amine; 2 chloro n (3 ethynylphenyl)pyrimidin 4 amine; 2 chloro n (4 phenoxyphenyl)pyrimidin 4 amine; 2 chloro n [4 chloro 3 (trifluoromethyl)phenyl] 6,7 dimethoxyquinazolin 4 amine; 2 chloro n [4 chloro 3 (trifluoromethyl)phenyl]pyrimidin 4 amine; 3 (2 chloro 6,7 dimethoxyquinazolin 4 ylamino)phenol; 4 (2 chloro 6,7 dimethoxyquinazolin 4 ylamino) 3 methyphenol; 4 [3 (2 chloro 6,7 dimethoxyquinazolin 4 ylamino)phenoxy]benzonitrile; cancerous inhibitor of PP2A protein; epidermal growth factor; erlotinib; n benzyl 2 chloro 6,7 dimethoxyquinazolin 4 amine; n benzyl 2 chloropyrimidin 4 amine; n2 (3 chlorophenyl) n4 (ethynylphenyl) 6,7 dimethoxyquinazoline 2,4 diamine; n2 [4 chloro 3 (trifluoromethyl)phenyl] n4 (3 ethynylphenyl) 6,7 dimethoxyquinazoline 2,4 diamine; n2 benzyl n4 (ethynylphenyl) 6,7 dimethoxyquinazoline 2,4 diamine; n2,n4 bis(3 ethynylphenyl)pyrimidine 2,4 diamine; n2,n4 bis[4 chloro 3 (trifluoromethyl)phenyl]pyrimidine 2,4 diamine; n4 (3 ethynylphenyl) 6,7 dimethoxy n2 (4 phenoxyphenyl)quinazoline 2,4 diamine; n4 (ethynylphenyl) n2 (2 fluoro 5 methylphenyl) 6,7 dimethoxyquinazoline 2,4 diamine; oncoprotein; protein kinase B; pyrimidine derivative; quinazoline derivative; unclassified drug; unindexed drug; antiproliferative activity; article; cancer cell; cancer inhibition; cell death; cell proliferation; cell viability; colony formation; controlled study; down regulation; drug potency; drug screening; drug structure; drug synthesis; enzyme activity; enzyme inhibition; human; human cell; intracellular signaling; liver cell carcinoma; protein expression; structure activity relation; substitution reaction; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Humans; Protein Phosphatase 2; Pyrimidines; Quinazolines; Receptor, Epidermal Growth Factor; Structure-Activity Relationship
Type
journal article