Design, synthesis and evaluation of the osimertinib analogue (C-005) as potent EGFR inhibitor against NSCLC

Ping Zhou; Gang Chen; Minqi Gao; Jiaquan Wu

doi:10.1016/j.bmc.2018.10.018

Design, synthesis and evaluation of the osimertinib analogue (C-005) as potent EGFR inhibitor against NSCLC

Bioorg Med Chem. 2018 Dec 15;26(23-24):6135-6145. doi: 10.1016/j.bmc.2018.10.018. Epub 2018 Oct 21.

Authors

Ping Zhou¹, Gang Chen², Minqi Gao³, Jiaquan Wu⁴

Affiliations

¹ Wuxi Shuangliang Biotechnology Co., Ltd., Jiangyin, Jiangsu Province 214437, People's Republic of China.
² Nanjing Galaxy Biological Technology Co., Ltd., Nanjing, Jiangsu 210032, People's Republic of China.
³ Wuxi Biortus Biosciences Co., Ltd., Jiangyin, Jiangsu Province 214437, People's Republic of China.
⁴ Wuxi Shuangliang Biotechnology Co., Ltd., Jiangyin, Jiangsu Province 214437, People's Republic of China; Wuxi Biortus Biosciences Co., Ltd., Jiangyin, Jiangsu Province 214437, People's Republic of China. Electronic address: jwu@shuangliang.com.

PMID: 30442506
DOI: 10.1016/j.bmc.2018.10.018

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.

Keywords: Epidermal growth factor receptor; N-demethyl metabolite; Non-small-cell lung cancer; Osimertinib; Pyrrolo-pyridine headpiece.

MeSH terms

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

Substances

Acrylamides
Aniline Compounds
Antineoplastic Agents
Piperazines
Protein Kinase Inhibitors
osimertinib
EGFR protein, human
ErbB Receptors