5VAL

BRAF in Complex with N-(3-(tert-butyl)phenyl)-4-methyl-3-(6-morpholinopyrimidin-4-yl)benzamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.26 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

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.

Nishiguchi, G.A.Rico, A.Tanner, H.Aversa, R.J.Taft, B.R.Subramanian, S.Setti, L.Burger, M.T.Wan, L.Tamez, V.Smith, A.Lou, Y.Barsanti, P.A.Appleton, B.A.Mamo, M.Tandeske, L.Dix, I.Tellew, J.E.Huang, S.Mathews Griner, L.A.Cooke, V.G.Van Abbema, A.Merritt, H.Ma, S.Gampa, K.Feng, F.Yuan, J.Wang, Y.Haling, J.R.Vaziri, S.Hekmat-Nejad, M.Jansen, J.M.Polyakov, V.Zang, R.Sethuraman, V.Amiri, P.Singh, M.Lees, E.Shao, W.Stuart, D.D.Dillon, M.P.Ramurthy, S.

(2017) J Med Chem 60: 4869-4881

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01862
  • Primary Citation of Related Structures:  
    5VAL, 5VAM

  • PubMed 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.


  • Organizational Affiliation

    Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase B-raf
A, B
281Homo sapiensMutation(s): 0 
Gene Names: BRAFBRAF1RAFB1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P15056 (Homo sapiens)
Explore P15056 
Go to UniProtKB:  P15056
PHAROS:  P15056
GTEx:  ENSG00000157764 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP15056
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
92D
Query on 92D

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-(3-tert-butylphenyl)-4-methyl-3-[6-(morpholin-4-yl)pyrimidin-4-yl]benzamide
C26 H30 N4 O2
MVCIEOOXCBYSMB-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.26 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.121α = 90
b = 94.121β = 90
c = 163.537γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
Cootmodel building
BUSTERrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-06-28
    Type: Initial release
  • Version 1.1: 2017-07-05
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references