Discovery of a series of novel phenylpiperazine derivatives as EGFR TK inhibitors.
Human epidermal growth factor receptor (EGFR) is an important drug target that plays a fundamental role in signal transduction pathways in oncology. We report herein the discovery of a novel class of phenylpiperazine derivatives with improved potency toward EGFR. The biological activity of compound 3p as inhibitor of EGFR was further investigated both in vitro and in vivo. Notably, compound 3p exhibited an IC50 in the nanomolar range in A549 cell cultures and induced a cessation of tumor growth with no toxicity, as determined by loss of body weight and death of treated mice. Compoutational docking studies also showed that compound 3p has interaction with EGFR key residues in the active site.
School of Life Sciences, Shandong University of Technology, Zibo, China.|State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, P. R. China.
Juan
J
Sun
School of Life Sciences, Shandong University of Technology, Zibo, China.
Xin-Yi
XY
Wang
School of Life Sciences, Shandong University of Technology, Zibo, China.|State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, P. R. China.
Peng-Cheng
PC
Lv
School of Life Sciences, Shandong University of Technology, Zibo, China.|State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, P. R. China.
Hai-Liang
HL
Zhu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; C031503:phenylpiperazine