5HU9

Crystal structure of ABL1 in complex with CHMFL-074


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.186 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)

Liu, F.Wang, B.Wang, Q.Qi, Z.Chen, C.Kong, L.L.Chen, J.Y.Liu, X.Wang, A.Hu, C.Wang, W.Wang, H.Wu, F.Ruan, Y.Qi, S.Liu, J.Zou, F.Hu, Z.Wang, W.Wang, L.Zhang, S.Yun, C.H.Zhai, Z.Liu, J.Liu, Q.

(2016) Oncotarget 7: 45562-45574

  • DOI: https://doi.org/10.18632/oncotarget.10037
  • Primary Citation of Related Structures:  
    5HU9

  • PubMed Abstract: 

    BCR gene fused ABL kinase is the critical driving force for the Philadelphia Chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) and has been extensively explored as a drug target. With a structure-based drug design approach we have discovered a novel inhibitor CHMFL-074, that potently inhibits both the native and a variety of clinically emerged mutants of BCR-ABL kinase. The X-ray crystal structure of CHMFL-074 in complex with ABL1 kinase (PDB ID: 5HU9) revealed a typical type II binding mode (DFG-out) but relatively rare hinge binding. Kinome wide selectivity profiling demonstrated that CHMFL-074 bore a high selectivity (S score(1) = 0.03) and potently inhibited ABL1 kinase (IC50: 24 nM) and PDGFR α/β (IC50: 71 nM and 88 nM). CHMFL-074 displayed strong anti-proliferative efficacy against BCR-ABL-driven CML cell lines such as K562 (GI50: 56 nM), MEG-01 (GI50: 18 nM) and KU812 (GI50: 57 nM). CHMFL-074 arrested cell cycle into the G0/G1 phase and induced apoptosis in the Ph+ CML cell lines. In addition, it potently inhibited the CML patient primary cell's proliferation but did not affect the normal bone marrow cells. In the CML cell K562 inoculated xenograft mouse model, oral administration of 100 mg/kg/d of CHMFL-074 achieved a tumor growth inhibition (TGI) of 65% without exhibiting apparent toxicity. As a potential drug candidate for fighting CML, CHMFL-074 is under extensive preclinical safety evaluation now.


  • Organizational Affiliation

    High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ABL1277Homo sapiensMutation(s): 0 
Gene Names: ABL1ABLJTK7
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P00519 (Homo sapiens)
Explore P00519 
Go to UniProtKB:  P00519
PHAROS:  P00519
GTEx:  ENSG00000097007 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00519
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
66K
Query on 66K

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(trifluoromethyl)benzamide
C32 H36 F3 N5 O3
CBLZTDLZCXMNCE-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
P [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
66K Binding MOAD:  5HU9 Kd: 24.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.186 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.852α = 90
b = 108.435β = 90
c = 146.295γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data processing
PHASERphasing
Cootmodel building
HKL-3000data reduction
HKL-3000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Science Foundation of ChinaChina31270769
National Basic Research Program of ChinaChina2012CB917202

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-13
    Type: Initial release
  • Version 1.1: 2016-12-28
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Refinement description