6316-09-2Relevant articles and documents
Heterocyclic compounds as well as preparation method and application thereof
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Paragraph 0191; 0192; 0193, (2018/07/30)
The invention belongs to the field of medicines and particularly relates to heterocyclic compounds with the structural characteristics shown in formula (I) or pharmaceutically acceptable salts, a preparation method and an application of the heterocyclic compounds as a nucleotide oxidative damage repairase MTH1 inhibitor. Pharmacological experiment results indicate that the compounds have significant inhabitation effects on the activity of MTH1 and can be used for preventing and treating clinical diseases related to MTH1.
Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors
Medina, Jesús R.,Becker, Christopher J.,Blackledge, Charles W.,Duquenne, Celine,Feng, Yanhong,Grant, Seth W.,Heerding, Dirk,Li, William H.,Miller, William H.,Romeril, Stuart P.,Scherzer, Daryl,Shu, Arthur,Bobko, Mark A.,Chadderton, Antony R.,Dumble, Melissa,Gardiner, Christine M.,Gilbert, Seth,Liu, Qi,Rabindran, Sridhar K.,Sudakin, Valery,Xiang, Hong,Brady, Pat G.,Campobasso, Nino,Ward, Paris,Axten, Jeffrey M.
experimental part, p. 1871 - 1895 (2011/05/30)
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
CHEMICAL COMPOUNDS
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Page/Page column 88, (2010/11/04)
The invention is directed to to substituted indazole derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R1 - R6 and X are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of disorders characterized by constitutively activated ACG kinases such as cancer and more specifically leukemia and cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.