6HD6

ABL1 IN COMPLEX WITH COMPOUND6 AND IMATINIB (STI-571)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.178 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1.

Schoepfer, J.Jahnke, W.Berellini, G.Buonamici, S.Cotesta, S.Cowan-Jacob, S.W.Dodd, S.Drueckes, P.Fabbro, D.Gabriel, T.Groell, J.M.Grotzfeld, R.M.Hassan, A.Q.Henry, C.Iyer, V.Jones, D.Lombardo, F.Loo, A.Manley, P.W.Pelle, X.Rummel, G.Salem, B.Warmuth, M.Wylie, A.A.Zoller, T.Marzinzik, A.L.Furet, P.

(2018) J Med Chem 61: 8120-8135

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01040
  • Primary Citation of Related Structures:  
    6HD4, 6HD6

  • PubMed Abstract: 

    Chronic myelogenous leukemia (CML) arises from the constitutive activity of the BCR-ABL1 oncoprotein. Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site have transformed CML into a chronic manageable disease. However, some patients develop drug resistance due to ATP-site mutations impeding drug binding. We describe the discovery of asciminib (ABL001), the first allosteric BCR-ABL1 inhibitor to reach the clinic. Asciminib binds to the myristate pocket of BCR-ABL1 and maintains activity against TKI-resistant ATP-site mutations. Although resistance can emerge due to myristate-site mutations, these are sensitive to ATP-competitive inhibitors so that combinations of asciminib with ATP-competitive TKIs suppress the emergence of resistance. Fragment-based screening using NMR and X-ray yielded ligands for the myristate pocket. An NMR-based conformational assay guided the transformation of these inactive ligands into ABL1 inhibitors. Further structure-based optimization for potency, physicochemical, pharmacokinetic, and drug-like properties, culminated in asciminib, which is currently undergoing clinical studies in CML patients.


  • Organizational Affiliation

    Novartis Institutes for BioMedical Research, Novartis Campus , CH-4056 Basel , Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ABL1
A, B
293Mus musculusMutation(s): 0 
Gene Names: Abl1Abl
EC: 2.7.10.2
UniProt
Find proteins for P00520 (Mus musculus)
Explore P00520 
Go to UniProtKB:  P00520
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00520
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
STI
Query on STI

Download Ideal Coordinates CCD File 
E [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
FYH
Query on FYH

Download Ideal Coordinates CCD File 
D [auth A]3-(morpholin-4-ylmethyl)-~{N}-[4-(trifluoromethyloxy)phenyl]benzamide
C19 H19 F3 N2 O3
MYWULUKAXYAFSH-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
STI BindingDB:  6HD6 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 60 assay(s)
EC50: min: 34, max: 1000 (nM) from 4 assay(s)
FYH BindingDB:  6HD6 Kd: 2000 (nM) from 1 assay(s)
IC50: 550 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.178 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.08α = 73.3
b = 65.201β = 79.82
c = 66.347γ = 84.54
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-12
    Type: Initial release
  • Version 1.1: 2018-10-10
    Changes: Data collection, Database references