- Discovery of 2-aminopyridines bearing a pyridone moiety as potent ALK inhibitors to overcome the crizotinib-resistant mutants
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Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In this work, a series of 2-aminopyridine derivatives were designed and synthesized by C-5 position incorporation of a 2-pyridone moiety and bioisosteric replacement of the C-3 position linkers. Optimization of the 2-aminopyridine derivatives led to the identification of hit 18d displaying a significant growth inhibition against a variety of ALK-addicted cancer cells. Especially in the case of ALK-positive Karpas-299 cell, 18d exhibited excellent anti-proliferative potency with an IC50 value of about 40 nM. Moreover, 18d demonstrated encouraging activities against wild-type ALK (19 nM), ROS1 (2.3 nM) as well as challenging crizotinib-resistant ALKL1196M and ALKG1202R mutants with IC50 values of 45 nM and 22 nM, respectively. Additionally flow cytometric analysis indicates that 18d inhibited Karpas-299 cell viability via G1 phase arrest. Taken together, this work provided a promising ALK inhibitor to circumvent the clinical crizotinib-resistant mutants.
- Chen, Wenteng,Guo, Xiao,Zhang, Can,Ke, Di,Zhang, Guolin,Yu, Yongping
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- Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2
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Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC50 = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC50 = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.
- Wang, Wanqi,Diao, Yanyan,Li, Wenjie,Luo, Yating,Yang, Tingyuan,Zhao, Yuyu,Qi, TianTian,Xu, Fangling,Ma, Xiangyu,Ge, Huan,Liang, Yingfan,Zhao, Zhenjiang,Liang, Xin,Wang, Rui,Zhu, Lili,Li, Honglin,Xu, Yufang
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supporting information
p. 1507 - 1513
(2019/04/17)
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- SUBSTITUTED 2-AMINOPYRIDINE PROTEIN KINASE INHIBITOR
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Disclosed are a 2-aminopyridine derivative having protein kinase inhibition activity, a preparation method and a pharmaceutical composition thereof Also disclosed are uses of the compounds and the pharmaceutical compositions thereof in the preparation of drugs for treating and/or preventing protein kinase-related diseases.
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Paragraph 0110
(2015/12/19)
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- Inhibitors of nedd8-activating enzyme
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The invention relates to an administration unit comprising crystalline form I of {(1 S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (I-216) hydrochloride salt and to a packaging comprising the administration unit according to the invention.
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- AMINO HETEROARYL COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF
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The present invention refers to aminoheteroaryl compounds of the following formula (I) as well as the preparation method and use thereof, wherein R1 and R3 are defined in the Description in details. The aminoheteroaryl compounds of t
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- Aminoheteroaryl compounds and preparation method and use thereof
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The present invention refers to aminoheteroaryl compounds of the following formula (I) as well as the preparation method and use thereof, wherein R1 and R3 are defined in the Description in details. The aminoheteroaryl compounds of t
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- SPIROCYCLIC MOLECULES AS PROTEIN KINASE INHIBITORS
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The present invention relates to spirocyclic compounds of formula I, namely spirocyclic (1H-pyrazol-4-yl)-3-(1-(2,6-dichloro-3-fiuorophenyl) ethoxy)pyridin-2-amines having protein kinase inhibitory activity, and methods of synthesizing and using such compounds. Preferred compounds are c-Met and/or ALK inhibitors useful for the treatment of abnormal cell growth, such as cancers
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- PYRIDINE COMPOUNDS AS INHIBITORS OF KINASE
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Disclosed are pyridines, their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds and compositions of the present invention have protein kinases inhibitory activities and are expected to be useful for the treatment of protein kinases mediated diseases and conditions.
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- CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
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The present invention relates to the use of ROS kinase inhibitors for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS by administration of crizotinib.
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- Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)
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Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.
- Cui, J. Jean,Tran-Dubé, Michelle,Shen, Hong,Nambu, Mitchell,Kung, Pei-Pei,Pairish, Mason,Jia, Lei,Meng, Jerry,Funk, Lee,Botrous, Iriny,McTigue, Michele,Grodsky, Neil,Ryan, Kevin,Padrique, Ellen,Alton, Gordon,Timofeevski, Sergei,Yamazaki, Shinji,Li, Qiuhua,Zou, Helen,Christensen, James,Mroczkowski, Barbara,Bender, Steve,Kania, Robert S.,Edwards, Martin P.
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p. 6342 - 6363
(2011/11/05)
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- AMINOHETEROARYL COMPOUNDS AS FOR THE TREATMENT OF DISEASES MEDIATED BY C-MET KINASE ACTIVITY
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Compounds of formula (I), are inhibitors of c-Met kinase activity, useful inter alia in the treatment of hyperproliferative diseases: wherein X is -N= or -CH=; ring A is optionally substituted mono- or bi-cyclic aryl or heteroaryl having from 5 to 12 ring
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Page/Page column 36
(2008/12/05)
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- PYRAZOLE-SUBSTITUTED AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Compounds of formula (1) are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.
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Page/Page column 56
(2010/10/20)
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- AMINOHETEROARYL COMPOUNDS AS PROTEIN TYROSINE KINASE INHIBITORS
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Aminoheteroaryl compounds are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.
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Page/Page column 47
(2010/10/20)
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- AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Aminopyridine and aminopyrazine compounds of formula (1), compositions including these compounds, and methods of their use are provided. Preferred compounds of formula 1 have activity as protein kinase inhibitors, including as inhibitors of c-MET.
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Page 93; 131
(2010/02/08)
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