RRC ID 68844
Author Zhou P, Chen G, Gao M, Wu J.
Title Design, synthesis and evaluation of the osimertinib analogue (C-005) as potent EGFR inhibitor against NSCLC.
Journal Bioorg Med Chem
Abstract Osimertinib has been approved as a first-line treatment for non-small-cell lung cancer (NSCLC) patients whose tumor carries EGFR activation and / or resistant mutations. To mitigate Osimertinib's toxicity caused by AZ5104, the N-demethylation metabolite of Osimertinib, we designed and synthesized a series of Osimertinib analogs with different headpieces. In vitro and in vivo analysis rendered a potential clinical candidate C-005 which had pyrrolo-pyridine headpiece. Biochemically, C-005 and its main human hepatocyte metabolite showed over 30 fold selectivity of L858R/T790M mutant EGFR over WT EGFR. Such selectivity profile was retained at cellular level. In general, C-005 is 2-14 fold more selective than Osimertinib in a panel of WT EGFR cancer cell lines. Furthermore, C-005 demonstrated robust antitumor efficacy and good tolerability in NCI-H1975, PC-9 and HCC827 xenograft mouse models, making it a potential candidate for human test in clinical.
Volume 26(23-24)
Pages 6135-6145
Published 2018-12-15
DOI 10.1016/j.bmc.2018.10.018
PII S0968-0896(18)31501-3
PMID 30442506
MeSH Acrylamides Aniline Compounds Animals Antineoplastic Agents / chemical synthesis Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Carcinoma, Non-Small-Cell Lung / drug therapy* Carcinoma, Non-Small-Cell Lung / metabolism Carcinoma, Non-Small-Cell Lung / pathology Cell Proliferation / drug effects Dose-Response Relationship, Drug Drug Design* Drug Screening Assays, Antitumor ErbB Receptors / antagonists & inhibitors ErbB Receptors / genetics ErbB Receptors / metabolism Female Humans Lung Neoplasms / drug therapy* Lung Neoplasms / metabolism Lung Neoplasms / pathology Mice Mice, Nude Molecular Structure Neoplasms, Experimental / drug therapy Neoplasms, Experimental / metabolism Neoplasms, Experimental / pathology Piperazines / chemical synthesis Piperazines / chemistry Piperazines / pharmacology* Protein Kinase Inhibitors / chemical synthesis Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology* Structure-Activity Relationship Tumor Cells, Cultured
IF 3.073
Human and Animal Cells PC-9(RCB4455)