Design and Discovery of N-(2-Methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers.

Autor:	Nishiguchi GA; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Rico A; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Tanner H; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Aversa RJ; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Taft BR; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Subramanian S; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Setti L; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Burger MT; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Wan L; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Tamez V; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Smith A; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Lou Y; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Barsanti PA; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Appleton BA; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Mamo M; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Tandeske L; Oncology, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Dix I; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG , Werk Klybeck, Postfach, CH-4002 Basel, Switzerland., Tellew JE; Genomics Institute of the Novartis Research Foundation , 10675 John Hopkins Drive, San Diego, California 92121, United States., Huang S; Genomics Institute of the Novartis Research Foundation , 10675 John Hopkins Drive, San Diego, California 92121, United States., Mathews Griner LA; Oncology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Cooke VG; Oncology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Van Abbema A; Oncology, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Merritt H; Oncology, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Ma S; Oncology, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Gampa K; Oncology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Feng F; Oncology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Yuan J; Oncology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Wang Y; Oncology, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Haling JR; Genomics Institute of the Novartis Research Foundation , 10675 John Hopkins Drive, San Diego, California 92121, United States., Vaziri S; Genomics Institute of the Novartis Research Foundation , 10675 John Hopkins Drive, San Diego, California 92121, United States., Hekmat-Nejad M; Oncology, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Jansen JM; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Polyakov V; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Zang R; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Sethuraman V; Oncology, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Amiri P; Oncology, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Singh M; Oncology, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Lees E; Oncology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Shao W; Oncology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Stuart DD; Oncology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Dillon MP; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Ramurthy S; Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2017 Jun 22; Vol. 60 (12), pp. 4869-4881. Date of Electronic Publication: 2017 Jun 08.
DOI:	10.1021/acs.jmedchem.6b01862
Abstrakt:	RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.
Databáze:	MEDLINE
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