844443-80-7Relevant articles and documents
Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors
Lin, Tingting,Li, Jiacheng,Liu, Liping,Li, Yuanqing,Jiang, Hualiang,Chen, Kaixian,Xu, Pan,Luo, Cheng,Zhou, Bing
, (2021/02/26)
Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 i
Design and synthesis of 4-(Heterocyclic substituted amino)-1h-pyrazole-3-carboxamide derivatives and their potent activity against acute myeloid leukemia (AML)
Zhi, Yanle,Wang, Zhijie,Yao, Chao,Li, Baoquan,Heng, Hao,Cai, Jiongheng,Xiang, Li,Wang, Yue,Lu, Tao,Lu, Shuai
, (2019/11/21)
Fms-like receptor tyrosine kinase 3 (FLT3) has been emerging as an attractive target for the treatment of acute myeloid leukemia (AML). By modifying the structure of FN-1501, a potent FLT3 inhibitor, 24 novel 1H-pyrazole-3-carboxamide derivatives were designed and synthesized. Compound 8t showed strong activity against FLT3 (IC50: 0.089 nM) and CDK2/4 (IC50: 0.719/0.770 nM), which is more efficient than FN-1501(FLT3, IC50: 2.33 nM; CDK2/4, IC50: 1.02/0.39 nM). Compound 8t also showed excellent inhibitory activity against a variety of FLT3 mutants (IC50 50: 1.22 nM). In addition, compound 8t significantly inhibited the proliferation of most human cell lines of NCI60 (GI50 1 μM for most cell lines). Taken together, these results demonstrated the potential of 8t as a novel compound for further development into a kinase inhibitor applied in cancer therapeutics.
Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H- pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design
Wyatt, Paul G.,Woodhead, Andrew J.,Berdini, Valerio,Boulstridge, John A.,Carr, Maria G.,Cross, David M.,Davis, Deborah J.,Devine, Lindsay A.,Early, Theresa R.,Feltell, Ruth E.,Lewis, E. Jonathan,McMenamin, Rachel L.,Navarro, Eva F.,O'Brien, Michael A.,O'Reilly, Marc,Reule, Matthias,Saxty, Gordon,Seavers, Lisa C. A.,Smith, Donna-Michelle,Squires, Matt S.,Trewartha, Gary,Walker, Margaret T.,Woolford, Alison J.-A.
experimental part, p. 4986 - 4999 (2009/08/16)
The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.
