5KYK

Covalent GTP-competitive inhibitors of KRAS G12C: Guanosine bisphosphonate Analogs


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.314 
  • R-Value Work: 0.267 
  • R-Value Observed: 0.270 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Covalent Guanosine Mimetic Inhibitors of G12C KRAS.

Xiong, Y.Lu, J.Hunter, J.Li, L.Scott, D.Choi, H.G.Lim, S.M.Manandhar, A.Gondi, S.Sim, T.Westover, K.D.Gray, N.S.

(2017) ACS Med Chem Lett 8: 61-66

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00373
  • Primary Citation of Related Structures:  
    5KYK

  • PubMed Abstract: 

    Ras proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure-activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound 11 , which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake. The SAR and crystallographic results reaffirm the exquisite molecular recognition that exists in the diphosphate region of RAS for guanosine nucleotides which must be considered in the design of nucleotide-competitive inhibitors.


  • Organizational Affiliation

    Department of Cancer Biology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase KRas
A, B, C
169Homo sapiensMutation(s): 1 
Gene Names: KRASKRAS2RASK2
UniProt & NIH Common Fund Data Resources
Find proteins for P01116 (Homo sapiens)
Explore P01116 
Go to UniProtKB:  P01116
PHAROS:  P01116
GTEx:  ENSG00000133703 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01116
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6ZD
Query on 6ZD

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B],
F [auth C]
5'-O-[(R)-[({2-[(chloroacetyl)amino]ethyl}sulfamoyl)methyl](hydroxy)phosphoryl]guanosine
C15 H23 Cl N7 O10 P S
AYYURYDKBCGXDD-FRJWGUMJSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.314 
  • R-Value Work: 0.267 
  • R-Value Observed: 0.270 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 114.83α = 90
b = 66.155β = 112.98
c = 98.006γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data collection
HKL-2000data scaling
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
V Scholar ResearchUnited StatesWel I-1829

Revision History  (Full details and data files)

  • Version 1.0: 2017-04-12
    Type: Initial release
  • Version 1.1: 2023-10-04
    Changes: Data collection, Database references, Refinement description