5NCY

mPI3Kd IN COMPLEX WITH inh1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.224 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Design and Synthesis of Soluble and Cell-Permeable PI3K delta Inhibitors for Long-Acting Inhaled Administration.

Perry, M.W.D.Bjorhall, K.Bonn, B.Carlsson, J.Chen, Y.Eriksson, A.Fredlund, L.Hao, H.Holden, N.S.Karabelas, K.Lindmark, H.Liu, F.Pemberton, N.Petersen, J.Rodrigo Blomqvist, S.Smith, R.W.Svensson, T.Terstiege, I.Tyrchan, C.Yang, W.Zhao, S.Oster, L.

(2017) J Med Chem 60: 5057-5071

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00401
  • Primary Citation of Related Structures:  
    5NCY, 5NCZ

  • PubMed Abstract: 

    PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesized to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work, we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimization for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC 50 > 9), and by careful manipulation of the pK a and lipophilicity, we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in vivo studies where significant target engagement could be demonstrated.


  • Organizational Affiliation

    Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform939Mus musculusMutation(s): 0 
Gene Names: Pik3cd
EC: 2.7.1.153
UniProt
Find proteins for O35904 (Mus musculus)
Explore O35904 
Go to UniProtKB:  O35904
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO35904
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8TK
Query on 8TK

Download Ideal Coordinates CCD File 
E [auth A]4-azanyl-6-[[(1~{S})-1-(3-methyl-5-oxidanylidene-6-phenyl-[1,3]thiazolo[3,2-a]pyridin-7-yl)ethyl]amino]pyrimidine-5-carbonitrile
C21 H18 N6 O S
XLCBQUCCOPILIO-ZDUSSCGKSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8TK BindingDB:  5NCY IC50: min: 0.4, max: 0.79 (nM) from 2 assay(s)
Binding MOAD:  5NCY IC50: 0.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.224 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 140.989α = 90
b = 64.549β = 103.59
c = 116.013γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-06-21 
  • Deposition Author(s): Petersen, J.

Revision History  (Full details and data files)

  • Version 1.0: 2017-06-21
    Type: Initial release
  • Version 1.1: 2017-07-05
    Changes: Database references