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Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFRL858R/T790M inhibitors. 2021

Jianheng Li, and Baijiao An, and Xianheng Song, and Qianzhong Zhang, and Chun Chen, and Shuxian Wei, and Runzhu Fan, and Xingshu Li, and Yong Zou
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.

Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFRL858R/T790M inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC50 value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC50 value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFRL858R/T790M-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.

UI MeSH Term Description Entries
D008297 Male Males
D008819 Mice, Nude Mutant mice homozygous for the recessive gene "nude" which fail to develop a thymus. They are useful in tumor studies and studies on immune responses. Athymic Mice,Mice, Athymic,Nude Mice,Mouse, Athymic,Mouse, Nude,Athymic Mouse,Nude Mouse
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D009374 Neoplasms, Experimental Experimentally induced new abnormal growth of TISSUES in animals to provide models for studying human neoplasms. Experimental Neoplasms,Experimental Neoplasm,Neoplasm, Experimental
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships

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