Design, synthesis and evaluation of the osimertinib analogue (C-005) as potent EGFR inhibitor against NSCLC. Issue 23 (15th December 2018)

• Record Type: Journal Article
• Authors: Zhou, Ping; Chen, Gang; Gao, Minqi; Wu, Jiaquan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 23/24(2018)
• Page Start: 6135
• Page End: 6145
• Publication Date: 2018-12-15
• Subjects: Osimertinib -- Pyrrolo-pyridine headpiece -- N-demethyl metabolite -- Non-small-cell lung cancer -- Epidermal growth factor receptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.10.018
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.