Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

Journal of Medicinal Chemistry

Volumn 59, Issue 3, 2016, Pages 1078-1101

  Mallinger, Aurélie ^a   Schiemann, Kai ^b   Rink, Christian ^a   Stieber, Frank ^b   Calderini, Michel ^b   Crumpler, Simon ^a   Stubbs, Mark ^a   Adeniji Popoola, Olajumoke ^a   Poeschke, Oliver ^b   Busch, Michael ^b   Czodrowski, Paul ^b   Musil, Djordje ^b   Schwarz, Daniel ^b   Ortiz Ruiz, Maria Jesus ^a   Schneider, Richard ^b   Thai, Ching ^a   Valenti, Melanie ^a   De Haven Brandon, Alexis ^a   Burke, Rosemary ^a   Workman, Paul ^a   Dale, Trevor ^c   Wienke, Dirk ^b   Clarke, Paul A ^a   Esdar, Christina ^b   Raynaud, Florence I ^a   Eccles, Suzanne A ^a   Rohdich, Felix ^b   Blagg, Julian ^a   more..

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^b MERCK KGAA   (Germany)

^c CARDIFF UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINOPYRIDINE DERIVATIVE; 3,4,5 TRISUBSTITUTED 2 AMINOPYRIDINE DERIVATIVE; 4 CHLORO 3,5 DIIODOPYRIDINE; 5 BROMO 3,4 DICHLORO N,N BIS(4 METHOXYBENZYL)PYRIDIN 2 AMINE; 5 BROMO 3,4 DICHLOROPYRIDIN 2 AMINE; 5 [5 CHLORO 4 [1 (2 METHOXYETHYL) 1,8 DIAZASPIRO[4.5]DECAN 8 YL]PYRIDIN 3 YL] 1 METHYL 1,3 DIHYDROBENZO[C]ISOTHIAZOLE 2,2 DIOXIDE; 8 (2 AMINO 5 CHLORO 3 FLUOROPYRIDIN 4 YL) 2,8 DIAZASPIRO [4.5]DECAN 1 ONE; 8 (3 BROMO 5 CHLOROPYRIDIN 4 YL) 1 (2 METHOXYETHYL) 1,8 DIAZASPIRO[4.5]DECANE; 8 (3 BROMO 5 CHLOROPYRIDIN 4 YL) 1 OXA 3,8 DIAZASPIRO[4.5]DECAN 2 ONE; 8 (3 BROMO 5 FLUOROPYRIDIN 4 YL) 1 OXA 3,8 DIAZASPIRO[4.5]DECAN 2 ONE; 8 (3 BROMO 5 FLUOROPYRIDIN 4 YL) 2,8 DIAZOSPIRO[4.5]DECAN 1 ONE; 8 (3,5 DIIODOPYRIDIN 4 YL) 1 OXA 3,8 DIAZASPIRO[4.5]DECAN 2 ONE; 8 [2 AMINO 3 CHLORO 5 (1 METHYL 1H INDAZOL 5 YL)PYRIDIN 4 YL] 2,8 DIAZOSPIRO[4.5]DECAN 1 ONE; 8 [2 AMINO 3 CHLORO 5 [4 [1 (2 HYDROXY 2 METHYLPROPYL) 1H PYRAZOL 4 YL]PHENYL]PYRIDIN 4 YL]DIAZASPIRO[4.5]DECAN 1 ONE; 8 [2 AMINO 3 FLUORO 5 (1 METHYL 2,2 DIOXIDO 1,3 DIHYDROBENZO[C]ISOTHIAZOL 5 YL)PYRIDIN 4 YL] 2,8 DIAZASPIRO[4.5]DECAN 1 ONE; 8 [2 [BIS(4 METHOXYBENZYL)AMINO] 5 BROMO 3 CHLOROPYRIDIN 4 YL] 2,8 DIAZASPIRO[4.5]DECAN 1 ONE; 8 [3 (3 AMINO 1H INDAZOL 6 YL) 5 CHLOROPYRIDIN 4 YL] 2,8 DIAZASPIRO[4.5]DECAN 1 ONE; 8 [3 CHLORO 5 (1 METHYL 2,2 DIOXIDO 1,3 DIHYDROBENZO[C]ISOTHIAZOL 5 YL)PYRIDIN 4 YL] 1 OXA 3,8 DIAZOSPIRO[4.5]DECAN 2 ONE; 8 [3 CHLORO 5 (1 METHYL 2,2 DIOXIDO 1,3 DIHYDROBENZO[C]ISOTHIAZOL 5 YL)PYRIDIN 4 YL] 2,8 DIAZASPIRO[4.5]DECAN 1 ONE; 8 [3 FLUORO 5 (1 METHYL 2,2 DIOXIDO 1,3 DIHYDROBENZO[C]ISOTHIAZOL 5 YL)PYRIDIN 4 YL] 1 OXA 3,8 DIAZASPIRO[4.5]DECAN 2 ONE; 8 [3 FLUORO 5 (1 METHYL 2,2 DIOXIDO 1,3 DIHYDROBENZO[C]ISOTHIAZOL 5 YL)PYRIDIN 4 YL] 2,8 DIAZASPIRO[4.5]DECAN 1 ONE; 8 [3 IODO 5 (TRIFLUOROMETHYL)PYRIDIN 4 YL] 1 OXA 3,8 DIAZASPIRO[4.5]DECAN 2 ONE; 8 [3 [4 (1 METHYL 1H PYRAZOL 4 YL)PHENYL] 5 (TRIFLUOROMETHYL)PYRIDIN 4 YL] 1 OXA 3,8 DIAZASPIRO[4.5]DECAN 2 ONE 2,2,2 TRIFLUOROACETATE; ANTINEOPLASTIC AGENT; CYCLIN DEPENDENT KINASE; CYCLIN DEPENDENT KINASE 19; CYCLIN DEPENDENT KINASE 8; CYCLIN DEPENDENT KINASE INHIBITOR; MEDIATOR COMPLEX; UNCLASSIFIED DRUG; UNINDEXED DRUG; ALPHA-AMINOPYRIDINE; AMINOPYRIDINE DERIVATIVE; CDK19 PROTEIN, HUMAN; CDK8 PROTEIN, HUMAN; MOLECULAR LIBRARY;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BINDING AFFINITY; COLORECTAL CARCINOMA; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG ELIMINATION; DRUG HALF LIFE; DRUG POTENCY; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG STRUCTURE; EMBRYO; FEMALE; HUMAN; HUMAN CELL; IC50; IN VITRO STUDY; IN VIVO STUDY; MALE; MEDICINAL CHEMISTRY; METABOLIC CLEARANCE; MOUSE; NONHUMAN; PHYSICAL CHEMISTRY; RAT; TUMOR XENOGRAFT; ADMINISTRATION AND DOSAGE; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOAVAILABILITY; CACO-2 CELL LINE; CHEMICAL STRUCTURE; CHEMISTRY; DOG; DOSE RESPONSE; DRUG DEVELOPMENT; DRUG SCREENING; METABOLISM; MOLECULAR LIBRARY; MOLECULAR MODEL; NEOPLASMS, EXPERIMENTAL; ORAL DRUG ADMINISTRATION; PATHOLOGY; PHARMACOLOGY; SOLUBILITY; STRUCTURE ACTIVITY RELATION; WISTAR RAT;

ADMINISTRATION, ORAL; AMINOPYRIDINES; ANIMALS; BIOLOGICAL AVAILABILITY; CACO-2 CELLS; CYCLIN-DEPENDENT KINASE 8; CYCLIN-DEPENDENT KINASES; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; FEMALE; HUMANS; MALE; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NEOPLASMS, EXPERIMENTAL; RATS; RATS, WISTAR; SMALL MOLECULE LIBRARIES; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84958211316     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01685     Document Type: Article

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