16153-81-4Relevant articles and documents
New 2,6,9-trisubstituted purine derivatives as Bcr-Abl and Btk inhibitors and as promising agents against leukemia
Bertrand, Jeanluc,Castro, Alejandro,Dostálová, Hana,Espinosa-Bustos, Christian,Jorda, Radek,Krystof, Vladimir,María Zarate, Ana,Mella, Jaime,Salas, Cristian O.
, (2019)
Bcr-Abl and Btk kinases are among the targets that have been considered for the treatment of leukemia. Therefore, several strategies have focused on the use of inhibitors as chemotherapeutic tools to treat these types of leukemia, such as imatinib (for Bcr-Abl) or ibrutinib (for Btk). However, the efficacy of these drugs has been reduced due to resistance mechanisms, which have motivated the development of new and more effective compounds. In this study, we designed, synthesized and evaluated 2,6,9-trisubstituted purine derivatives as novel Bcr-Abl and Btk inhibitors. We identified 5c and 5d as potent inhibitors of both kinases (IC50 values of 40 nM and 0.58/0.66 μM for Abl and Btk, respectively). From docking and QSAR analyses, we concluded that fluorination of the arylpiperazine system is detrimental to the activity against two kinases, and we also validated our hypothesis that the substitution on the 6-phenylamino ring is important for the inhibition of both kinases. In addition, our studies indicated that most compounds could suppress the proliferation of leukemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos cells) at low micromolar concentrations in vitro. Finally, we preliminarily demonstrated that 5c inhibited the downstream signaling of both kinases in the respective cell models. Therefore, 5c or 5d possessed potency to be further optimized as anti-leukemia drugs by simultaneously inhibiting the Bcr-Abl and Btk kinases.
Discovery and in Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor
Chen, Xing,Yan, Yaoyao,Zhang, Zhaoyan,Zhang, Faming,Liu, Mingming,Du, Leran,Zhang, Haixia,Shen, Xiaobao,Zhao, Dahai,Shi, Jing Bo,Liu, Xinhua
, p. 11857 - 11885 (2021/09/02)
Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor"was described with hit finding, structure optimization, and lead discovery. Starting with hit 14, structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro. Also, compound 54 (with cathepsin C Enz IC50 = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.
NOVEL SULFONAMIDE DERIVATIVE WITH FUSED PYRIMIDINE SKELETON, HAVING EPIDERMAL GROWTH FACTOR RECEPTOR MUTATION INHIBITORY EFFECT
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Paragraph 0076; 0082, (2021/07/02)
The present invention relates to a novel fused pyrimidine based sulfonamide derivative represented by Formula I, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition including the same as an active ingredient. The novel fused pyrimidine based sulfonamide derivative of the present invention can effectively suppress the growth of cancer cells and resistance to drugs, which are induced by mutations in the tyrosine kinase domain of epidermal growth factor receptors, or the growth of cancer cells having such resistance.
TRICYCLIC KINASE INHIBITORS AND USE THEREOF
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Paragraph 0209-0211, (2021/03/13)
The present application provides novel compounds that are inhibitors of kinases, including AMPK-related kinases like NUAK1, NUAK2, SIK1, SIK2, SIK3, MARK1, MARK2, MARK3, MARK4, as well as AURKA, AURKB, AURKC, CLK1, CLK2, DCAMKL2, MAPK7, MKNK2, PIK3CD, PKN3, RET, TAOK1, TAOK2, TAOK3, ULK2 and their mutants. The application also provides compositions, including pharmaceutical compositions, kits that include compounds, and methods of making and using compounds. The compounds provided herein are useful in treating diseases, disorders, or conditions that are mediated by these kinases.