ABSTRACT
HER2 kinase as a well-established target for breast cancer (BC) therapy is associated with aggressive clinical outcomes; thus, herein we present structural optimization for HER2-selective targeting. HER2 profiling of the developed derivatives demonstrated potent and selective inhibitions (IC50: 5.4-12 nM) compared to lapatinib (IC50: 95.5 nM). Favorably, 17d exhibited minimum off-target kinase activation. NCI-5-dose screening revealed broad-spectrum activities (GI50: 1.43-2.09 µM) and 17d had a remarkable selectivity toward BC. Our compounds revealed significant selective and potent antiproliferative activities (â¼20-fold) against HER2+ (AU565, BT474) compared to HER2(-) cells. At 0.1 IC50, 15i, 17d, and 25b inhibited pERK1/2 and pAkt by immunoblotting. Furthermore, 17d demonstrated potent in vivo tumor regression against the BT474 xenograft model. Notably, a metastasis case was observed in the vehicle but not in the test mice groups. CD-1 mice metabolic stability assay revealed high stability and low intrinsic clearance of 17d (T1/2 > 145 min and CLint(mic) < 9.6 mL/min/kg).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Drug Design , Lapatinib/chemistry , Molecular Targeted Therapy , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Animals , Apoptosis , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , Humans , In Vitro Techniques , Mice , Mice, Nude , Receptor, ErbB-2/metabolism , Signal Transduction , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Four series of some 4-substituted-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives 5a-f, 6a-f, 8a-f, and 9a-f were designed to be screened for their antitumor activity. All compounds were evaluated against breast (MCF-7) and lung (A-549) cell lines. Six compounds 5a, 5b, 6b, 6e, 9e, and 9f displaying activity against both cell lines were further estimated for their EGFR-TK inhibitory activity where they revealed 41-91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP-binding site of EGFR-TK demonstrated their binding mode where H-bonding interaction with Met793 through N(1) of pyrimidine or N(2) of pyrazole was observed.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Antineoplastic Agents/chemistry , Binding Sites , Cell Line, Tumor , Cell Survival/drug effects , Enzyme Activation/drug effects , ErbB Receptors/metabolism , Humans , Hydrogen Bonding , MCF-7 Cells , Molecular Docking Simulation , Protein Kinase Inhibitors/chemistry , Protein Structure, Tertiary , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
Several analogues of the general formulae 2-methoxy-9-substituted acridine and 6-chloro-2-methoxy-9-substituted acridine were synthesized and evaluated in vitro at 6.25 microg/mL against M. tuberculosis H37Rv. Compounds 15 and 17 showed potential antitubercular activity with 100% inhibition to the virulent mycobacterium.
