1022956-26-8Relevant articles and documents
Discovery of a potent dual ALK and EGFR T790M inhibitor
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.
, p. 497 - 510 (2017)
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.
Small molecule inhibitors of leucine-rich repetitive kinase 2 and their applications
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Paragraph 0078-0082, (2022/01/07)
The present invention provides a small molecule inhibitor of leucine-rich repetitive kinase 2 and applications thereof; compounds as small molecule inhibitors such as compounds shown in formula I of the present invention or isotopic forms thereof, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs. The compound has a high LRRK2 inhibitory activity and has high application value in the preparation of drugs for the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and other diseases.
AXL KINASE INHIBITORS AND USE OF THE SAME
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Page/Page column 162; 213; 283, (2019/10/29)
Tartrate salts of the compound of structure (I), crystalline forms thereof, and therapeutic applications thereof for treating solid tumors (e.g., advanced solid tumor) or hematopoietic cancers. Also provided herein are methods for synthesizing the tartrat
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
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
, p. 674 - 697 (2017/08/30)
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.
