2,4-Diarylamino-pyrimidines as kinase inhibitors co-targeting IGF1R and EGFR(L⁸⁵⁸R/T⁷⁹⁰M)

Shingpan Chan; Kun Han; Rong Qu; Linjiang Tong; Yingjun Li; Zhang Zhang; Huimin Cheng; Xiaoyun Lu; Adam Patterson; Jeff Smaill; Xiaomei Ren; Jian Ding; Hua Xie; Ke Ding

doi:10.1016/j.bmcl.2015.07.089

2,4-Diarylamino-pyrimidines as kinase inhibitors co-targeting IGF1R and EGFR(L⁸⁵⁸R/T⁷⁹⁰M)

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4277-81. doi: 10.1016/j.bmcl.2015.07.089. Epub 2015 Jul 30.

Authors

Shingpan Chan¹, Kun Han², Rong Qu³, Linjiang Tong², Yingjun Li¹, Zhang Zhang⁴, Huimin Cheng⁵, Xiaoyun Lu⁵, Adam Patterson⁶, Jeff Smaill⁶, Xiaomei Ren⁵, Jian Ding², Hua Xie⁷, Ke Ding⁸

Affiliations

¹ 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.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ 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.
⁴ 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.
⁵ State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
⁶ Auckland Cancer Society Research Centre, and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, #92019 Private Bag, Auckland 1142, New Zealand.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: hxie@simm.ac.cn.
⁸ 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.

PMID: 26259806
DOI: 10.1016/j.bmcl.2015.07.089

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.

Keywords: Dual inhibitor; EGFR; IGF1R; NSCLC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor, IGF Type 1
Receptors, Somatomedin / antagonists & inhibitors*
Receptors, Somatomedin / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
IGF1R protein, human
Protein Kinase Inhibitors
Receptors, Somatomedin
EGFR protein, human
ErbB Receptors
Receptor, IGF Type 1