- 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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- 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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- 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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- 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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