761440-65-7Relevant articles and documents
Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance
Finlay, M. Raymond V.,Barton, Peter,Bickerton, Sue,Bista, Michal,Colclough, Nicola,Cross, Darren A. E.,Evans, Laura,Floc’h, Nicolas,Gregson, Clare,Guérot, Carine M.,Hargreaves, David,Kang, Xiaoming,Lenz, Eva M.,Li, Xu,Liu, Yi,Lorthioir, Olivier,Martin, Matthew J.,McKerrecher, Darren,McWhirter, Claire,O’Neill, Daniel,Orme, Jonathan P.,Mosallanejad, Arash,Rahi, Amar,Smith, Paul D.,Talbot, Verity,Ward, Richard A.,Wrigley, Gail,Wylot, Marta,Xue, Lin,Yao, Tieguang,Ye, Yang,Zhao, Xiliang
, p. 13704 - 13718 (2021/09/28)
The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, andin vivoactivity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.
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.
supporting information, 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.
Preparation method of ALK inhibitor Brigatinib
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Paragraph 0051-0054, (2020/06/02)
The invention relates to the technical field of medicines, and relates to a preparation method of a medicine ALK inhibitor AP26113. The method comprises the following steps: (1) carrying out substitution reaction of aromatic amine on 2,4,5-trichloropyrimi