347161-75-5Relevant academic research and scientific papers
Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)- N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors
Liu, Qingsong,Wu, Yun,Wang, Beilei,Wang, Junjie,Qi, Shuang,Zou, Fengming,Qi, Ziping,Liu, Feiyang,Liu, Qingwang,Chen, Cheng,Hu, Chen,Hu, Zhenquan,Wang, Aoli,Wang, Li,Wang, Wenchao,Ren, Tao,Cai, Yujiao,Bai, Mingfeng,Liu, Jing
, p. 6083 - 6101 (2019/08/02)
Starting from our previously developed c-KIT kinase inhibitor CHMFL-KIT-8140, through a type II kinase inhibitor binding element hybrid design approach, we discovered a novel c-KIT kinase inhibitor compound 18 (CHMFL-KIT-64), which is potent against c-KIT wt and a broad spectrum of drug-resistant mutants with improved bioavailability. 18 exhibits single-digit nM potency against c-KIT kinase and c-KIT T670I mutants in the biochemical assay and displays great potencies against most of the gain-of-function mutations in the juxtamembrane domain, drug-resistant mutations in the ATP binding pocket (except V654A), and activation loops (except D816V). In addition, 18 exhibits a good in vivo pharmacokinetic (PK) profile in different species including mice, rats, and dogs. It also displays good in vivo antitumor efficacy in the c-KIT T670I, D820G, and Y823D mutant-mediated mice models as well as in the c-KIT wt patient primary cells which are known to be imatinib-resistant. The potent activity against a broad spectrum of clinically important c-KIT mutants combining the good in vivo PK/pharmacodynamic properties of 18 indicates that it might be a new potential therapeutic candidate for gastrointestinal stromal tumors.
Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: Synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N′-{4-(4-quinolyloxy)phenyl}ureas
Kubo, Kazuo,Shimizu, Toshiyuki,Ohyama, Shin-Ichi,Murooka, Hideko,Iwai, Akemi,Nakamura, Kazuhide,Hasegawa, Kazumasa,Kobayashi, Yoshiko,Takahashi, Noriko,Takahashi, Kazumi,Kato, Shinichiro,Izawa, Toshio,Isoe, Toshiyuki
, p. 1359 - 1366 (2007/10/03)
N-Phenyl-N′-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC50 value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRα and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.
