- EGFR INHIBITORS, COMPOSITIONS AND METHODS THERE OF
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The present invention relates to compounds of Formula I, methods of using the compounds as EGFR inhibitors, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders s
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Page/Page column 18-19; 28-29
(2020/10/20)
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- 2,4,5-substituted pyrimidine compound as well as preparation method and application thereof
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The invention relates to a 2,4,5-substituted pyrimidine compound as well as a preparation method and application thereof, and provides pharmaceutically acceptable salt, solvate, stereoisomer or prodrug molecule thereof, wherein the molecular structure of the pharmaceutically acceptable salt, solvate, stereoisomer or prodrug molecule is shown in the specification. The provided 2,4,5-substituted pyrimidine compound is low in cytotoxicity, has high selective inhibition on EGFR, can inhibit the proliferation of EGFR drug-resistant mutant enzymes (such as T790M/L858R/C797S mutant enzymes) and cellstrains thereof at a low concentration (such as nano mole concentration), can be used for treating diseases caused by EGFR mutation, and can be made into a new generation of EGFR inhibitors.
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- Discovery of a potent dual ALK and EGFR T790M inhibitor
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The mutational activations of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) are validated oncogenic events and the targets of approved drugs to treat non-small cell lung cancer (NSCLC). Here we report highly potent dual small molecule inhibitors of both ALK and EGFR, particularly the T790M mutant which confers resistance to first generation EGFR inhibitors. Dual ALK/EGFR inhibitors may provide an efficient approach to prevent resistance that arises as a consequence of clinically reported reciprocal activation mechanisms. Our lead compound 7c displayed remarkable inhibitory activities against both ALK and EGFR in enzymatic and cellular assays. We demonstrate that 7c is capable of recapitulating the signaling effects and antiproliferative activity of combined treatment with the approved ALK inhibitor ceritinib and T790M EGFR inhibitor osimertinib against patient-derived non-small cell lung cancer cell line, DFCI032 which harbors both EML4-ALK and activated EGFR.
- Jang, Jaebong,Son, Jung Beom,To, Ciric,Bahcall, Magda,Kim, So Young,Kang, Seock Yong,Mushajiang, Mierzhati,Lee, Younho,J?nne, Pasi A.,Choi, Hwan Geun,Gray, Nathanael S.
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p. 497 - 510
(2017/05/22)
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- Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC
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Recently, more and more concomitant EGFR mutations and ALK rearrangement are observed from the clinic, which still lacks effective single-agent therapy. Starting from ALK inhibitor 14 (TAE684), we have developed a highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q, L1196M, F1174L and C1156Y mutants biochemically. Compound 18 significantly inhibited the proliferation of EGFR mutant and EML4-ALK driven NSCLC cell lines. In the cellular context it strongly affected EGFR and ALK mediated signaling pathways, induced apoptosis and arrested cell cycle at G0/G1 phase. In the in vivo studies, 18 significantly suppressed the tumor growth in H1975 cell inoculated xenograft model (40 mg/kg/d, TGI: 99%) and H3122 cell inoculated xenograft model (40 mg/kg/d, TGI: 78%). Compound 18 might be a potential drug candidate for EGFR- or ALK-individual as well as concomitant EGFR/ALK NSCLC.
- Chen, Yongfei,Wu, Jiaxin,Wang, Aoli,Qi, Ziping,Jiang, Taoshan,Chen, Cheng,Zou, Fengming,Hu, Chen,Wang, Wei,Wu, Hong,Hu, Zhenquan,Wang, Wenchao,Wang, Beilei,Wang, Li,Ren, Tao,Zhang, Shanchun,Liu, Qingsong,Liu, Jing
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p. 674 - 697
(2017/08/30)
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- COMPOUNDS FOR INHIBITING CELL PROLIFERATION IN EGFR-DRIVEN CANCERS
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The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of Formula (I), wherein the variables are as defined herein.
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- COMPOUNDS FOR INHIBITING CELL PROLIFERATION IN EGFR-DRIVEN CANCERS
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The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of formula (I), wherein the variables are as defined herein.
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