6KLA

Crystal structure of human c-KIT kinase domain in complex with compound 15a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.187 

wwPDB Validation 3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia.

Lin, W.H.Wu, S.Y.Yeh, T.K.Chen, C.T.Song, J.S.Shiao, H.Y.Kuo, C.C.Hsu, T.Lu, C.T.Wang, P.C.Wu, T.S.Peng, Y.H.Lin, H.Y.Chen, C.P.Weng, Y.L.Kung, F.C.Wu, M.H.Su, Y.C.Huang, K.W.Chou, L.H.Hsueh, C.C.Yen, K.J.Kuo, P.C.Huang, C.L.Chen, L.T.Shih, C.Tsai, H.J.Jiaang, W.T.

(2019) J Med Chem 62: 11135-11150

  • DOI: 10.1021/acs.jmedchem.9b01229
  • Primary Citation of Related Structures:  
    6KLA

  • PubMed Abstract: 
  • Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these ...

    Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a , with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.


    Organizational Affiliation

    Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C.



Macromolecules
Find similar proteins by:  (by identity cutoff)  |  Structure
Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
Mast/stem cell growth factor receptor KitA331Homo sapiensMutation(s): 0 
Gene Names: KITSCFR
EC: 2.7.10.1
Find proteins for P10721 (Homo sapiens)
Explore P10721 
Go to UniProtKB:  P10721
NIH Common Fund Data Resources
PHAROS  P10721
Protein Feature View
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
DJX
Query on DJX

Download CCD File 
A
N-[6-(4-ethylpiperazin-1-yl)-2-methyl-pyrimidin-4-yl]-5-pyridin-4-yl-1,3-thiazol-2-amine
C19 H23 N7 S
MBWHJBDHRADERX-UHFFFAOYSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.187 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.205α = 90
b = 63.205β = 90
c = 196.142γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History 

  • Version 1.0: 2019-11-27
    Type: Initial release
  • Version 1.1: 2020-01-08
    Changes: Database references