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Mallinger, Aurélie; Schiemann, Kai; Rink, Christian; Stieber, Frank; Calderini, Michel; Crumpler, Simon; Stubbs, Mark; Adeniji-Popoola, Olajumoke; Poeschke, Oliver; Busch, Michael; Czodrowski, Paul; Musil, Djordje; Schwarz, Daniel; Ortiz-Ruiz, Maria-Jesus; Schneider, Richard; Thai, Ching; Valenti, Melanie; de Haven Brandon, Alexis; Burke, Rosemary; Workman, Paul; Dale, Trevor; Wienke, Dirk; Clarke, Paul A; Esdar, Christina; Raynaud, Florence I; Eccles, Suzanne A; Rohdich, Felix; Blagg, Julian
Journal of medicinal chemistry, 02/2016, Letnik: 59, Številka: 3Journal Article
The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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