5DWR

Identification of N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1,2 and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Identification of N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies.

Burger, M.T.Nishiguchi, G.Han, W.Lan, J.Simmons, R.Atallah, G.Ding, Y.Tamez, V.Zhang, Y.Mathur, M.Muller, K.Bellamacina, C.Lindvall, M.K.Zang, R.Huh, K.Feucht, P.Zavorotinskaya, T.Dai, Y.Basham, S.Chan, J.Ginn, E.Aycinena, A.Holash, J.Castillo, J.Langowski, J.L.Wang, Y.Chen, M.Y.Lambert, A.Fritsch, C.Kauffmann, A.Pfister, E.Vanasse, K.G.Garcia, P.D.

(2015) J Med Chem 58: 8373-8386

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01275
  • Primary Citation of Related Structures:  
    5DWR

  • PubMed Abstract: 

    Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound 3, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies.


  • Organizational Affiliation

    Oncology Research, Novartis Institutes for Biomedical Research , CH-4056, Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase pim-1328Homo sapiensMutation(s): 0 
Gene Names: PIM1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P11309 (Homo sapiens)
Explore P11309 
Go to UniProtKB:  P11309
PHAROS:  P11309
GTEx:  ENSG00000137193 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11309
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5H7
Query on 5H7

Download Ideal Coordinates CCD File 
B [auth A]N-{4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide
C24 H23 F3 N4 O
VRQXRVAKPDCRCI-ZNMIVQPWSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Binding Affinity Annotations 
IDSourceBinding Affinity
5H7 Binding MOAD:  5DWR Ki: 1 (nM) from 1 assay(s)
BindingDB:  5DWR Ki: min: 6.00e-3, max: 1 (nM) from 2 assay(s)
IC50: min: 1, max: 6 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.175 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.233α = 90
b = 98.233β = 90
c = 81.123γ = 120
Software Package:
Software NamePurpose
BUSTERrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-11-11
    Type: Initial release
  • Version 1.1: 2015-11-25
    Changes: Database references