Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 25, Issue 19, Pages 4277-4281Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.07.089
Keywords
EGFR; IGF1R; NSCLC; Dual inhibitor
Categories
Funding
- Ministry of Science and Technology of China [2014DFG32100]
- National Natural Science Foundation of China [81425021, 81173080, 81321092]
- National High Technology Research and Development (863) for Young Scientists program of China [2015AA020906]
- Health Research Council of New Zealand [13/1020]
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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. (C) 2015 Elsevier Ltd. All rights reserved.
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