905306-05-0Relevant articles and documents
Dual nicotinamide phosphoribosyltransferase and epidermal growth factor receptor inhibitors for the treatment of cancer
Zhang, Wanheng,Zhang, Kuojun,Yao, Yiwu,Liu, Yunyao,Ni, Yong,Liao, Chenzhong,Tu, Zhengchao,Qiu, Yatao,Wang, Dexiang,Chen, Dong,Qiang, Lei,Li, Zheng,Jiang, Sheng
, (2020/11/27)
Multitarget drugs have emerged as a promising treatment modality in modern anticancer therapy. Taking advantage of the synergy of NAMPT and EGFR inhibition, we have developed the first compounds that serve as dual inhibitors of NAMPT and EGFR. On the basis of CHS828 and erlotinib, a series of hybrid molecules were successfully designed and synthesized by merging of the pharmacophores. Among the compounds that were synthesized, compound 28 showed good NAMPT and EGFR inhibition, and excellent in vitro anti-proliferative activity. Compound 28, which is a new chemotype devoid of a Michael receptor, strongly inhibited the proliferation of several cancer cell lines, including H1975 non-small cell lung cancer cells harboring the EGFRL858R/T790M mutation. More importantly, it imparted significant in vivo antitumor efficacy in a human NSCLC (H1975) xenograft nude mouse model. This study provides promising leads for the development of novel antitumor agents and valuable pharmacological probes for the assessment of dual inhibition in NAMPT and EGFR pathway with a single inhibitor.
Benzo nitrogen hetero-aromatic ring compound, and preparation method and applications thereof
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, (2018/03/01)
The invention belongs to the field of chemical medicine, and discloses a benzo nitrogen hetero-aromatic ring compound represented by formula I, or pharmaceutically acceptable salts, stereisomers, racemic compounds, prodrugs, or solvates thereof. The invention also discloses applications of the benzo nitrogen hetero-aromatic ring compound in preparation of drugs used for treating diseases caused byprotein kinase and/or nicotinamide phosphoribosyltransferase abnormal activity. The benzo nitrogen hetero-aromatic ring compound represented by formula I or the salts thereof possess tyrosine kinaseand Nampt double inhibition effects, can be taken as effective components in treatment or prevention of tumor, are excellent in curative effect, and low in toxic or side effect.
Design and Evaluation of Potent EGFR Inhibitors through the Incorporation of Macrocyclic Polyamine Moieties into the 4-Anilinoquinazoline Scaffold
Ju, Yilan,Wu, Jintao,Yuan, Xi,Zhao, Luqing,Zhang, Ganlin,Li, Chao,Qiao, Renzhong
, p. 11372 - 11383 (2019/01/04)
Adenosine triphosphate (ATP)-competitive inhibitors of the epidermal growth factor receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, some marketed drugs affect a transient beneficial response in EGFR mutant NSCLC patients. We reported a series of potential EGFR inhibitors through incorporation of macrocyclic polyamine into 4-anilinoquinazoline scaffold. It is expected that anilinoquinazoline part effectively bind to EGFR domain, while ATP molecules are captured by a macrocyclic polyamine moiety. In vitro experiments exhibited that most of tested compounds suppressed tumor cell proliferation more strongly than Gefitinib and Lapatinib (dual inhibitor of EGFR/HER2) as controls. In kinase assays, the compound 1f showed excellent dual inhibition activity toward EGFRWT (IC50 = 1.4 nM) and HER2 (IC50 = 2.1 nM). In vivo pharmacology evaluation of 1f showed significant antitumor activity (TGI = 44.2%) in A549 xenografts mice. The current work provided a feasible solution to optimize anilinoquinazoline-based inhibitors.