571189-49-6Relevant articles and documents
Discovery of Dual CDK6/PIM1 Inhibitors with a Novel Structure, High Potency, and Favorable Druggability for the Treatment of Acute Myeloid Leukemia
Yuan, Kai,Ji, Minghui,Xie, Shengnan,Qiu, Zhixia,Chen, Weijiao,Min, Wenjian,Xia, Fei,Zheng, Mingming,Wang, Xiao,Li, Jiaxing,Hou, Yi,Kuang, Wenbin,Wang, Liping,Gu, Wanjian,Li, Zhiyu,Yang, Peng
, p. 857 - 875 (2022/01/12)
Nowadays, the simultaneous inhibition of two or more pathways plays an increasingly important role in cancer treatment due to the complex and diverse pathogenesis of cancer, and the combination of the cyclin-dependent kinase 6 (CDK6) inhibitor and PIM1 inhibitor was found to generate synergistic effects in acute myeloid leukemia (AML) treatment. Therefore, we discovered a novel lead 1 targeting CDK6/PIM1 via pharmacophore-based and structure-based virtual screening, synthesized five different series of new derivates, and obtained a potent and balanced dual CDK6/PIM1 inhibitor 51, which showed high kinase selectivity. Meanwhile, 51 displayed an excellent safety profile and great pharmacokinetic properties. Furthermore, 51 displayed stronger potency in reducing the burden of AML than palbociclib and SMI-4a in vivo. In summary, we offered a new direction for AML treatment and provided a great lead compound for AML preclinical studies.
Pyrimidine-2, 4-diamine compound and preparation method and application thereof
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, (2021/06/09)
The invention discloses a pyrimidine-2, 4-diamine compound and a preparation method and application thereof, and relates to the technical field of medicinal chemistry, the pyrimidine-2, 4-diamine compound can be used for biological or pharmacological phenomena, cathepsin C participated signal channel conduction research, and evaluation of a novel cathepsin C inhibitor; in addition, through in-vitro and in-vivo anti-cathepsin C activity screening, the results show that the compound has relatively strong inhibitory activity on cathepsin C; through in-vivo anti-neutrophil serine protease activity screening, the result shows that the compound has relatively strong inhibitory activity on neutrophil serine protease; in-vivo anti-inflammatory activity screening results show that the compound has an effective treatment effect on an inflammatory disease model; meanwhile, the toxicity is low, and the application prospect is good.
Discovery of a Pyrimidothiazolodiazepinone as a Potent and Selective Focal Adhesion Kinase (FAK) Inhibitor
Groendyke, Brian J.,Nabet, Behnam,Mohardt, Mikaela L.,Zhang, Haisheng,Peng, Ke,Koide, Eriko,Coffey, Calvin R.,Che, Jianwei,Scott, David A.,Bass, Adam J.,Gray, Nathanael S.
, p. 30 - 38 (2021/01/11)
Focal adhesion kinase (FAK) is a tyrosine kinase with prominent roles in protein scaffolding, migration, angiogenesis, and anchorage-independent cell survival and is an attractive target for the development of cancer therapeutics. However, current FAK inhibitors display dual kinase inhibition and/or significant activity on several kinases. Although multitargeted activity is at times therapeutically advantageous, such behavior can also lead to toxicity and confound chemical-biology studies. We report a novel series of small molecules based on a tricyclic pyrimidothiazolodiazepinone core that displays both high potency and selectivity for FAK. Structure-activity relationship (SAR) studies explored modifications to the thiazole, diazepinone, and aniline "tail,"which identified lead compound BJG-03-025. BJG-03-025 displays potent biochemical FAK inhibition (IC50 = 20 nM), excellent kinome selectivity, activity in 3D-culture breast and gastric cancer models, and favorable pharmacokinetic properties in mice. BJG-03-025 is a valuable chemical probe for evaluation of FAK-dependent biology.