title: Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor.
abstract: Recent reports suggest that an increasing number of patients with lung cancer, especially those with activating mutations of the epidermal growth factor receptor (EGFR), also present with brain metastases and leptomeningeal metastases. These patients have poor prognosis as there are no approved drugs for these indications. Available agents have poor efficacy for these patients even at well above their standard dose. Herein, we report the discovery of (4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (2R)-2,4-dimethylpiperazine-1-carboxylate 1m (AZD3759), an investigational drug currently in Phase 1 clinical trial, which has excellent central nervous system penetration and which induces profound regression of brain metastases in a mouse model.
authors: Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development , 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors: Qingbei
authors: Q
authors: Zeng
authors: Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development , 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors: Jiabing
authors: J
authors: Wang
authors: Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development , 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors: Ziqiang
authors: Z
authors: Cheng
authors: Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development , 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors: Kan
authors: K
authors: Chen
authors: AstraZeneca Translational Centre, Personal Healthcare and Biomarkers iMed, AstraZeneca R&D, Karolinska Institutet , Department of Clinical Neuroscience, R5:U1 Karolinska University Hospital, SE-171 76 Stockholm, Sweden.|Karolinska Institutet , Department of Clinical Neuroscience, Centre for Psychiatry Research, R5:02 Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Peter
authors: P
authors: Johnström
authors: Karolinska Institutet , Department of Clinical Neuroscience, Centre for Psychiatry Research, R5:02 Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors: Katarina
authors: K
authors: Varnäs
authors: Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development , 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors: David Yunzhi
authors: DY
authors: Li
authors: Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development , 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors: Zhen Fan
authors: ZF
authors: Yang
authors: Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development , 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors: Xiaolin
authors: X
authors: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000556:secondary; D002490:Central Nervous System / Q000378:metabolism*; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D055808:Drug Discovery; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D023041:Xenograft Model Antitumor Assays
chemical_list: C000604577:AZD3759; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases