6NPU

C-abl Kinase domain with the activator(cmpd29), N-(1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)acetamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.33 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Identification and Optimization of Novel Small c-Abl Kinase Activators Using Fragment and HTS Methodologies.

Simpson, G.L.Bertrand, S.M.Borthwick, J.A.Campobasso, N.Chabanet, J.Chen, S.Coggins, J.Cottom, J.Christensen, S.B.Dawson, H.C.Evans, H.L.Hobbs, A.N.Hong, X.Mangatt, B.Munoz-Muriedas, J.Oliff, A.Qin, D.Scott-Stevens, P.Ward, P.Washio, Y.Yang, J.Young, R.J.

(2019) J Med Chem 62: 2154-2171

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01872
  • Primary Citation of Related Structures:  
    6NPE, 6NPU, 6NPV

  • PubMed Abstract: 

    Abelson kinase (c-Abl) is a ubiquitously expressed, nonreceptor tyrosine kinase which plays a key role in cell differentiation and survival. It was hypothesized that transient activation of c-Abl kinase via displacement of the N-terminal autoinhibitory "myristoyl latch", may lead to an increased hematopoietic stem cell differentiation. This would increase the numbers of circulating neutrophils and so be an effective treatment for chemotherapy-induced neutropenia. This paper describes the discovery and optimization of a thiazole series of novel small molecule c-Abl activators, initially identified by a high throughput screening. Subsequently, a scaffold-hop, which exploited the improved physicochemical properties of a dihydropyrazole analogue, identified through fragment screening, delivered potent, soluble, cell-active c-Abl activators, which demonstrated the intracellular activation of c-Abl in vivo.


  • Organizational Affiliation

    Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ABL1
A, B
298Homo 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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
STI
Query on STI

Download Ideal Coordinates CCD File 
C [auth A],
F [auth B]
4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE
C29 H31 N7 O
KTUFNOKKBVMGRW-UHFFFAOYSA-N
2PE
Query on 2PE

Download Ideal Coordinates CCD File 
J [auth B]NONAETHYLENE GLYCOL
C18 H38 O10
YZUUTMGDONTGTN-UHFFFAOYSA-N
KWV
Query on KWV

Download Ideal Coordinates CCD File 
D [auth A],
I [auth B]
~{N}-[2-(3,4-dichlorophenyl)-3,4-dihydropyrazol-5-yl]ethanamide
C11 H11 Cl2 N3 O
CQPBYZABXGBFMI-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth B]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth B],
H [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
STI BindingDB:  6NPU Ki: min: 13, max: 7000 (nM) from 5 assay(s)
Kd: min: 1, max: 1.00e+4 (nM) from 35 assay(s)
IC50: min: 1.1, max: 1.00e+4 (nM) from 68 assay(s)
EC50: min: 34, max: 1000 (nM) from 4 assay(s)
KWV BindingDB:  6NPU IC50: min: 316, max: 398 (nM) from 2 assay(s)
EC50: 794 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.33 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.093α = 90
b = 95.643β = 90
c = 115.535γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-03-13
    Type: Initial release
  • Version 1.1: 2024-03-13
    Changes: Data collection, Database references, Structure summary