5V9U

Crystal Structure of small molecule ARS-1620 covalently bound to K-Ras G12C


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.38 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.149 
  • R-Value Observed: 0.151 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

Janes, M.R.Zhang, J.Li, L.S.Hansen, R.Peters, U.Guo, X.Chen, Y.Babbar, A.Firdaus, S.J.Darjania, L.Feng, J.Chen, J.H.Li, S.Li, S.Long, Y.O.Thach, C.Liu, Y.Zarieh, A.Ely, T.Kucharski, J.M.Kessler, L.V.Wu, T.Yu, K.Wang, Y.Yao, Y.Deng, X.Zarrinkar, P.P.Brehmer, D.Dhanak, D.Lorenzi, M.V.Hu-Lowe, D.Patricelli, M.P.Ren, P.Liu, Y.

(2018) Cell 172: 578-589.e17

  • DOI: https://doi.org/10.1016/j.cell.2018.01.006
  • Primary Citation of Related Structures:  
    5V9U

  • PubMed Abstract: 

    KRAS G12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS G12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRAS G12C . ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRAS G12C -specific inhibitors with promising therapeutic potential.


  • Organizational Affiliation

    Wellspring Biosciences, San Diego, CA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase KRas
A, B
170Homo sapiensMutation(s): 4 
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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GDP
Query on GDP

Download Ideal Coordinates CCD File 
H [auth A],
P [auth B]
GUANOSINE-5'-DIPHOSPHATE
C10 H15 N5 O11 P2
QGWNDRXFNXRZMB-UUOKFMHZSA-N
91S
Query on 91S

Download Ideal Coordinates CCD File 
F [auth A],
M [auth B]
(S)-1-{4-[6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl] piperazin-1-yl}propan-1-one
C21 H19 Cl F2 N4 O2
ICXZXYUITXWHGD-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A],
J [auth B],
N [auth B],
O [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
I [auth A]
K [auth B]
C [auth A],
D [auth A],
E [auth A],
I [auth A],
K [auth B],
L [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.38 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.149 
  • R-Value Observed: 0.151 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 33.44α = 77.48
b = 39.74β = 81.97
c = 61.78γ = 77.2
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-07
    Type: Initial release
  • Version 1.1: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description