4ZZY

Structure of human PARP2 catalytic domain bound to an isoindolinone inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.219 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of 2-[1-(4,4-Difluorocyclohexyl)Piperidin-4-Yl]-6-Fluoro-3-Oxo-2,3-Dihydro-1H-Isoindole-4-Carboxamide (Nms-P118): A Potent, Orally Available and Highly Selective Parp- 1 Inhibitor for Cancer Therapy.

Papeo, G.M.E.Posteri, H.Borghi, D.Busel, A.A.Caprera, F.Casale, E.Ciomei, M.Cirla, A.Corti, E.D'Anello, M.Fasolini, M.Forte, B.Galvani, A.Isacchi, A.Khvat, A.Krasavin, M.Y.Lupi, R.Orsini, P.Perego, R.Pesenti, E.Pezzetta, D.Rainoldi, S.Riccardi-Sirtori, F.Scolaro, A.Sola, F.Zuccotto, F.Felder, E.R.Donati, D.Montagnoli, A.

(2015) J Med Chem 58: 6875

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00680
  • Primary Citation of Related Structures:  
    4ZZX, 4ZZY, 4ZZZ, 5A00

  • PubMed Abstract: 

    The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.


  • Organizational Affiliation

    Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
POLY [ADP-RIBOSE] POLYMERASE 2363Homo sapiensMutation(s): 0 
EC: 2.4.2.30
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UGN5 (Homo sapiens)
Explore Q9UGN5 
Go to UniProtKB:  Q9UGN5
PHAROS:  Q9UGN5
GTEx:  ENSG00000129484 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UGN5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
D7N
Query on D7N

Download Ideal Coordinates CCD File 
B [auth A]2-[1-(4,4-Difluorocyclohexyl)-piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide
C20 H24 F3 N3 O2
ARYVAQSYRLZVQD-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
D7N BindingDB:  4ZZY Kd: 1389 (nM) from 1 assay(s)
Binding MOAD:  4ZZY Kd: 1389 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.219 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.377α = 90
b = 74.377β = 90
c = 148.463γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-12
    Type: Initial release
  • Version 1.1: 2015-09-23
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description