Discovery of Potent Antiproliferative Agents Targeting EGFR Tyrosine Kinase Based on the Pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidin-4-amine Scaffold

Abstract

A series of pyridothieno[3,2-d]pyrimidin-4-amines was designed and synthesized as congeners to the classical 4-anilinoquinazolines as ATP-competitive epidermal growth factor receptor (EGFR) inhibitors.Compound 5a exhibited the most potent and selective inhibitory activity against EGFR with an IC 50 value of 36.7 nM. Moreover, compounds 4b and 5a showed remarkable cell growth inhibition against leukemia, central nervous system cancer, and non-small cell lung cancer cell lines that overexpress EGFR, with growth inhibition of 50% (GI 50 ) values of around 10 nM in the full U.S. National Cancer Institute 60 cell panel assay. Cell cycle studies indicated that compounds 4b and 5a induced significant cell cycle arrest in the S-phase and G0/G1, respectively, in addition to boosting P27 kip expression. Compound 5a did not alter the viability of placental trophoblasts, which reflects its safety for normal cells. The standard COMPARE analyses demonstrated considerable correlation levels between compounds 4b and 5a and erlotinib, with pyridinium chlorochromate (PCC) values of 0.707 and 0.727, respectively. Key words pyridothieno[3,2-d]pyrimidine; epidermal growth factor receptor (EGFR); inhibitorThe epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) that plays a vital role in signaling pathways that regulate cellular growth, proliferation and survival.1) Such signaling pathways are triggered by a tightly regulated protein phosphorylation reaction. This reaction is initiated with the binding of the epidermal growth factor (EGF) to the extracellular domain of EGFR leading to the activation of its intrinsic kinase domain. The latter has the ability to activate proteins by removing phosphate groups from ATP and covalently binding them to tyrosine substrates of the proteins.2) Deregulation of this controlled pathway, through overexpression and/or mutation of EGFR, contributes to the malignant transformations of normal cells. Overexpression of EGFR has been observed in a large number of human cancers including breast, prostate, ovarian, colorectal, kidney, brain and non-small cell lung cancers. 3,4)Examples of clinically approved ATP-competitive EGFR inhibitors including gefitinib, lapatinib and erlotinib, are structurally based on a central 4-anilinoquinazoline scaffold 5) (Fig. 1). However the emerging resistance of cancer cells to current medicines derives our passion to search for novel congeners to the 4-anilinoquinazoline scaffold as a beached for cancer therapy.6,7) Structure-activity relationship studies of 4-anilinoquinazolinederivatives revealed that the quinazoline core fits into the ATP-competitive pocket of EGFR. 8,9) Consistent with this, some investigations showed that the isosteric replacement of the benzene ring of the quinazoline core with five-membered heteroaromatic rings is favorable.10,11) The flexibility of the linking NH group between the heteroaryl core and the aniline ring permits the proper orientation of the aniline ring into the hydrophobic pocket, lying in the b...

Madecassic Acid Derivatives as Potential Anticancer Agents: Synthesis and Cytotoxic Evaluation

“…The synthesized compounds were submitted to the NCI for evaluation of their cytotoxic activity against 60 human tumor cell lines. Nineteen of these compounds ( 1 , 2 , 3 , 6 , 8 , 10 , 12 , 15 , 17 , 18 , 21 , 22 , 24 , 25 , 26 , 27 , 28 , 29 , and 30 ) were selected for initial screening based on the diversity they added to the NCI small-molecule collection. − Results for each compound in the single-dose assay are reported in Tables S1 and S2 (Supporting Information). Thirteen of the tested compounds ( 2 , 3 , 6 , 8 , 10 , 12 , 15 , 17 , 25 , 26 , 27 , 28 , and 29 ) satisfied predetermined inhibition thresholds set by the NCI and were thus selected for complete dose–response studies with five different test concentrations (0.01, 0.1, 1, 10, and 100 μM).…”

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

“…Compound 181 was very potent as it exhibited an 81% inhibitory potential when compared to doxorubicin. It was further taken up for preclinical studies but failed due to a lack of specificity in the study model ( Aziz et al, 2015 ).…”

“…The presence of quinazoline fusion also improved the activity of the compound ( Zheng et al, 2010 ). The pyrido fused molecules were found to be weakly active ( Aziz et al, 2015 ).…”

11‐Substituted Benzo[c]phenanthridines: New Structures and Insight into Their Mode of Antiproliferative Action

“…The PCC values were calculated setting the GI 50 values as endpoints, determining am inimal correlation of 0.2, as tandard deviation of 0.05, and am inimum of 40 common cell lines scanned for both compounds. According to the literature, [22] well-correlated compounds were defined with PCCv alues > 0.60, thereby presumably possessing the same mechanismo fa ction. The resultso f the performed NCI-COMPARE studies are summarized in Ta ble 2.…”