174709-17-2Relevant articles and documents
Studying the Conformation of a Receptor Tyrosine Kinase in Solution by Inhibitor-Based Spin Labeling
Yin, Dongsheng M.,Hannam, Jeffrey S.,Schmitz, Anton,Schiemann, Olav,Hagelueken, Gregor,Famulok, Michael
, p. 8417 - 8421 (2017/07/11)
The synthesis of a spin label based on PD168393, a covalent inhibitor of a major anticancer drug target, the epidermal growth factor receptor (EGFR), is reported. The label facilitates the analysis of the EGFR structure in solution by pulsed electron paramagnetic resonance (EPR) spectroscopy. For various EGFR constructs, including near-full-length EGFR, we determined defined distance distributions between the two spin labels bound to the ATP binding sites of the EGFR dimer. The distances are in excellent agreement with an asymmetric dimer of the EGFR. Based on crystal structures, this dimer had previously been proposed to reflect the active conformation of the receptor but structural data demonstrating its existence in solution have been lacking. More generally, our study provides proof-of-concept that inhibitor-based spin labeling enables the convenient introduction of site-specific spin labels into kinases for which covalent or tight-binding small-molecule modulators are available.
Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting EGFR
Wu, Jianwei,Chen, Wenteng,Xia, Guangxin,Zhang, Jing,Shao, Jiaan,Tan, Biqin,Zhang, Chunchun,Yu, Wanwan,Weng, Qinjie,Liu, Haiyan,Hu, Miao,Deng, Hailin,Hao, Yu,Shen, Jingkang,Yu, Yongping
, p. 974 - 978 (2013/10/22)
This letter describes the construction of conformationally constrained quinazoline analogues. Structure-activity relationship studies led to the identification of the lead compound 9n. Compound 9n exhibits effective in vitro activity against A431WT,overexpression and H1975 [L858R/T790M] cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A549, and K562). Compound 9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of 9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of 9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.
Modified PEG-anilinoquinazoline derivatives as potential EGFR PET agents
Dissoki, Samar,Eshet, Renana,Billauer, Hana,Mishani, Eyal
body text, p. 41 - 52 (2009/12/01)
Inhibition of epidermal growth factor receptor tyrosine kinase (EGFR-TK) has emerged as a major approach for cancer-targeted therapy. Consequently, there has been a great interest in the use of labeled EGFR-TK inhibitors as positron emission tomography (P
High-affinity epidermal growth factor receptor (EGFR) irreversible inhibitors with diminished chemical reactivities as positron emission tomography (PET)-imaging agent candidates of EGFR overexpressing tumors
Mishani, Eyal,Abourbeh, Galith,Jacobson, Orit,Dissoki, Samar,Ben Daniel, Revital,Rozen, Yulia,Shaul, Mazal,Levitzki, Alexander
, p. 5337 - 5348 (2007/10/03)
Previous studies with the anilinoquinazoline epidermal growth factor receptor (EGFR) irreversible inhibitor [11C]-ML03 demonstrated a rapid metabolism of the tracer, which led to its low in vivo accumulation in EGFR overexpressing tumors. To enhance tumor uptake, the chemical structure of the compound was modified, and four new groups of EGFR inhibitors with a wide range of chemical reactivities were synthesized. Chemical reactivity assay of the compounds, performed with reduced glutathione (GSH), revealed that the group C (4-(dimethylamino)-but-2-enoic amide) derivative was the least chemically reactive against the nucleophilic attack of GSH. Nonetheless, it demonstrated a high inhibitory potency and bound irreversibly to the EGFR. Consequently, the blood stability of the group C compound (5a, ML04) labeled with 11C was studied. In a time frame of 60 min, no radioactive metabolites were detected in blood. The stability of [11C]-5a, as indicated both from in vitro blood-stability assays and injection into nude rats, was significantly higher as compared to [11C]-ML03. Since group C presented a greater promise for tumor accumulation, it represents, to date, the most suitable candidate for radiolabeling with long-lived positron emission tomography (PET) radioisotopes.
