6PGO

Crystal structure of human KRAS G12C covalently bound to a phthalazine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.218 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of a Covalent Inhibitor of KRASG12C(AMG 510) for the Treatment of Solid Tumors.

Lanman, B.A.Allen, J.R.Allen, J.G.Amegadzie, A.K.Ashton, K.S.Booker, S.K.Chen, J.J.Chen, N.Frohn, M.J.Goodman, G.Kopecky, D.J.Liu, L.Lopez, P.Low, J.D.Ma, V.Minatti, A.E.Nguyen, T.T.Nishimura, N.Pickrell, A.J.Reed, A.B.Shin, Y.Siegmund, A.C.Tamayo, N.A.Tegley, C.M.Walton, M.C.Wang, H.L.Wurz, R.P.Xue, M.Yang, K.C.Achanta, P.Bartberger, M.D.Canon, J.Hollis, L.S.McCarter, J.D.Mohr, C.Rex, K.Saiki, A.Y.San Miguel, T.Volak, L.P.Wang, K.H.Whittington, D.A.Zech, S.G.Lipford, J.R.Cee, V.J.

(2020) J Med Chem 63: 52-65

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b01180
  • Primary Citation of Related Structures:  
    6PGO, 6PGP

  • PubMed Abstract: 

    KRAS G12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS G12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRAS G12C inhibitor currently in phase I clinical trials (NCT03600883).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase KRas
A, B
183Homo 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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.218 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.565α = 90
b = 106.329β = 90
c = 33.736γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
HKL-2000data reduction
SCALEPACKdata scaling
HKL-2000data scaling
PHASERphasing
REFMACrefinement
Cootmodel building

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2019-12-25 
  • Deposition Author(s): Mohr, C.

Revision History  (Full details and data files)

  • Version 1.0: 2019-12-25
    Type: Initial release
  • Version 1.1: 2020-01-22
    Changes: Database references