- Design, synthesis and biological evaluation of WZ4002 analogues as EGFR inhibitors
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A series of thirty two anilinopyrimidines derived from WZ4002 has been synthesized and evaluated for percentage inhibition of six different EGFR kinases using LanthaScreen binding assay method (EGFR d746 – 750) or Z'LYTE assay method (EGFR-WT, EGFR d746 – 750, EGFR T790M, EGFR T790M L858R, EGFR C797S and EGFR T790M L858R C797S). Ortho-hydroxyacetamide 10 exhibited complete inhibition of all the six kinases at 10 μM. Against the triple mutant, EGFR T790M C797S L858R, compounds 9–12 exhibited complete inhibition at 10 μM and nearly complete inhibition at 1 μM. The target compounds were also evaluated using the MTT assay to determine their cytotoxic activity against human non-small cell lung cancer cells (PC9, PC9GR and H460) and mouse leukemic cells (Ba/F3 WT and Ba/F3T 3151). Overall, 7, 9–12, 30 and 31 were found to be the most potent compounds across all five cell lines.
- Romu, Aireen A.,Lei, Zining,Zhou, Bin,Chen, Zhe-Sheng,Korlipara, Vijaya
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p. 4832 - 4837
(2017/10/06)
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- Synthesis and evaluation of 2-anilinopyrimidines bearing 3-aminopropamides as potential epidermal growth factor receptor inhibitors
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Novel compounds 12a-i were synthesized and biologically evaluated. Several ones exhibited stronger inhibitory activity than gefitinib against EGFR L858R/T790M and antiproliferative effects on H1975 and HCC827 cells. The 3-aminopropamide in compounds like 12h could be converted to the active acrylamide in the presence of arginine. Importantly, 12h showed improved stability relative to compound 1 whose structure is same to 12h excepting an acrylamide moiety. Interestingly, 12i, a NO donating compound of 12h, showed more potent and selective inhibition than 12h on H1975 cells. Significantly, 12i produced high levels of NO in H1975 cells but not in non-tumorous 16HBE cells, and its inhibition was diminished by NO scavenger. Furthermore, 12i dose-dependently produced inhibitory effects on EGFR downstream signaling in H1975 cells.
- Han, Chun,Wan, Ledong,Ji, Hongbin,Ding, Ke,Huang, Zhangjian,Lai, Yisheng,Peng, Sixun,Zhang, Yihua
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- Discovery of selective irreversible inhibitors for EGFR-T790M
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Targeting the epidermal growth factor receptor kinase (EGFR) with ATP-competitive kinase inhibitors results in dramatic but short-lived responses in patients with EGFR mutant non small cell lung cancer. A series of novel covalent EGFR kinase inhibitors with selectivity for the clinically relevant T790M 'gatekeeper' resistance mutation relative to wild-type EGFR were discovered by library screening. A representative compound 3i was obtained through a systematic SAR study guided by mutant EGFR-dependent cellular proliferation assays.
- Zhou, Wenjun,Ercan, Dalia,Jaenne, Pasi A.,Gray, Nathanael S.
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p. 638 - 643
(2011/03/18)
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- EGFR INHIBITORS AND METHODS OF TREATING DISORDERS
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The present invention relates to novel pyrimidine, pyrrolo-pyrimidine, pyrrolo-pyridine, pyridine, purine and triazine compounds which are able to modulate epidermal growth factor receptor (EGFR), including Her-kinases, and the use of such compounds in the treatment of various diseases, disorders or conditions.
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Page/Page column 124-125
(2010/11/18)
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