2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Jun 22;60(12):4869-4881. doi: 10.1021/acs.jmedchem.6b01862.
Gisele A Nishiguchi 1,  Alice Rico 2,  Huw Tanner 2,  Robert J Aversa 1,  Benjamin R Taft 2,  Sharadha Subramanian 2,  Lina Setti 2,  Matthew T Burger 1,  Lifeng Wan 2,  Victoriano Tamez 1,  Aaron Smith 2,  Yan Lou 2,  Paul A Barsanti 2,  Brent A Appleton 2,  Mulugeta Mamo 2,  Laura Tandeske 3,  Ina Dix 4,  John E Tellew 5,  Shenlin Huang 5,  Lesley A Mathews Griner 6,  Vesselina G Cooke 6,  Anne Van Abbema 3,  Hanne Merritt 3,  Sylvia Ma 3,  Kalyani Gampa 6,  Fei Feng 6,  Jing Yuan 6,  Yingyun Wang 3,  Jacob R Haling 5,  Sepideh Vaziri 5,  Mohammad Hekmat-Nejad 3,  Johanna M Jansen 2,  Valery Polyakov 2,  Richard Zang 2,  Vijay Sethuraman 3,  Payman Amiri 3,  Mallika Singh 3,  Emma Lees 6,  Wenlin Shao 6,  Darrin D Stuart 6,  Michael P Dillon 1,  Savithri Ramurthy 2
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 2 Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
  • 3 Oncology, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
  • 4 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG , Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
  • 5 Genomics Institute of the Novartis Research Foundation , 10675 John Hopkins Drive, San Diego, California 92121, United States.
  • 6 Oncology, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
PMID: 28557458 DOI: 10.1021/acs.jmedchem.6b01862
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100510
    99.45%, RAF抑制剂
    Raf
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