6P8Z

Crystal structure of human KRAS G12C covalently bound to an acryloylazetidine acetamide inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.231 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery ofN-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C.

Shin, Y.Jeong, J.W.Wurz, R.P.Achanta, P.Arvedson, T.Bartberger, M.D.Campuzano, I.D.G.Fucini, R.Hansen, S.K.Ingersoll, J.Iwig, J.S.Lipford, J.R.Ma, V.Kopecky, D.J.McCarter, J.San Miguel, T.Mohr, C.Sabet, S.Saiki, A.Y.Sawayama, A.Sethofer, S.Tegley, C.M.Volak, L.P.Yang, K.Lanman, B.A.Erlanson, D.A.Cee, V.J.

(2019) ACS Med Chem Lett 10: 1302-1308

  • DOI: https://doi.org/10.1021/acsmedchemlett.9b00258
  • Primary Citation of Related Structures:  
    6P8W, 6P8X, 6P8Y, 6P8Z

  • PubMed Abstract: 

    KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. KRAS p.G12C , which occurs in approximately 14% of lung adenocarcinomas, 3-5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery of a class of novel, potent, and selective covalent inhibitors of KRAS G12C identified through a custom library synthesis and screening platform called Chemotype Evolution and structure-based design. Identification of a hidden surface groove bordered by H95/Y96/Q99 side chains was key to the optimization of this class of molecules. Best-in-series exemplars exhibit a rapid covalent reaction with cysteine 12 of GDP-KRAS G12C with submicromolar inhibition of downstream signaling in a KRAS G12C -specific manner.


  • Organizational Affiliation

    Departments of Therapeutic Discovery, Oncology Research, Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.


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
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
O5S (Subject of Investigation/LOI)
Query on O5S

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B]
2-[5-chloro-2-cyclopropyl-3-(5-methoxy-3,4-dihydroisoquinoline-2(1H)-carbonyl)-7-methyl-1H-indol-1-yl]-N-(1-propanoylazetidin-3-yl)acetamide
C31 H35 Cl N4 O4
DLHKDPGFCFXJMF-UHFFFAOYSA-N
GDP
Query on GDP

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B]
GUANOSINE-5'-DIPHOSPHATE
C10 H15 N5 O11 P2
QGWNDRXFNXRZMB-UUOKFMHZSA-N
CA
Query on CA

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

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.231 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.758α = 90
b = 65.392β = 105.09
c = 62.596γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
HKL-2000data reduction
SCALEPACKdata scaling
HKL-2000data scaling
PHASERphasing
REFMACrefinement
Cootmodel building

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2019-08-28 
  • Deposition Author(s): Mohr, C.

Revision History  (Full details and data files)

  • Version 1.0: 2019-08-28
    Type: Initial release
  • Version 1.1: 2019-10-02
    Changes: Data collection, Database references