6NO9

PIM1 in complex with Cpd16 (5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report

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This is version 1.2 of the entry. See complete history. 


Literature

Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.

Wang, X., Blackaby, W., Allen, V., Chan, G.K.Y., Chang, J.H., Chiang, P.C., Diene, C., Drummond, J., Do, S., Fan, E., Harstad, E.B., Hodges, A., Hu, H., Jia, W., Kofie, W., Kolesnikov, A., Lyssikatos, J.P., Ly, J., Matteucci, M., Moffat, J.G., Munugalavadla, V., Murray, J., Nash, D., Noland, C.L., Del Rosario, G., Ross, L., Rouse, C., Sharpe, A., Slaga, D., Sun, M., Tsui, V., Wallweber, H., Yu, S.F., Ebens, A.J.

(2019) J Med Chem 62: 2140-2153

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01857
  • Primary Citation of Related Structures:  
    6NO9

  • PubMed Abstract: 

    Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.

    • Organizational Affiliation: 

    Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase pim-1273Homo 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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KUV
Query on KUV
Download Ideal Coordinates CCD File 
E [auth A]5-amino-N-{5-[(4R,5R)-4-amino-5-fluoroazepan-1-yl]-1-methyl-1H-pyrazol-4-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide
C20 H22 F3 N7 O S
NHXVGMQFCYBLTL-ZWNOBZJWSA-N
PO4
Query on PO4
Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]		PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL
Download Ideal Coordinates CCD File 
B [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
KUV Binding MOAD:  6NO9 Ki: 0.03 (nM) from 1 assay(s)
BindingDB:  6NO9 Ki: min: 0.03, max: 0.04 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 96.632α = 90
b = 96.632β = 90
c = 80.703γ = 120
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-02-27
    Type: Initial release
  • Version 1.1: 2019-03-13
    Changes: Data collection, Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description