title: 2,4-Diarylamino-pyrimidines as kinase inhibitors co-targeting IGF1R and EGFR(L⁸⁵⁸R/T⁷⁹⁰M).
abstract: IGF1R amplification was recently implied to be related to the secondary acquired resistance against the 2nd or 3rd generation EGFR inhibitor therapies. We have successfully identified a series of 2,4-diarylamino-pyrimidines as new IGF1R/EGFR(L858R/T790M) co-targeting agents. One of the most promising compounds 8g potently inhibits both kinases with low nanomolar IC50 values, but is significantly less potent in inhibiting the wild type EGFR. The compound also displays a good kinase selectivity profile against a panel of 468 kinases. Moreover, 8g strongly suppresses the proliferation of CO-1686-resistant H1975-IGF1R cancer cells, suggesting its promising potential as a new lead compound for future anticancer drug discovery.
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, #19 Yuquan Road, Beijing 100049, China.
authors.forename: Shingpan
authors.initials: S
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Han
authors.affiliation: University of Chinese Academy of Sciences, #19 Yuquan Road, Beijing 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Qu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Linjiang
authors.initials: L
authors.lastname: Tong
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, #19 Yuquan Road, Beijing 100049, China.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China; Jinan University, #601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.affiliation: Auckland Cancer Society Research Centre, and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, #92019 Private Bag, Auckland 1142, New Zealand.
authors.forename: Adam
authors.initials: A
authors.lastname: Patterson
authors.affiliation: Auckland Cancer Society Research Centre, and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, #92019 Private Bag, Auckland 1142, New Zealand.
authors.forename: Jeff
authors.initials: J
authors.lastname: Smaill
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: hxie@simm.ac.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China. Electronic address: ding_ke@gibh.ac.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C000597236:IGF1R protein, human; D047428:Protein Kinase Inhibitors; D017451:Receptors, Somatomedin; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1
keywords: Dual inhibitor; EGFR; IGF1R; NSCLC