PDBsum entry 5ece

Transferase/transferase inhibitor

PDB id: 5ece

Contents

Protein chains

208 a.a.

Ligands

EDO ×7

5N2 ×3

ACT

Metals

_ZN ×4

Waters ×348

PDB id:

5ece

Name:

Transferase/transferase inhibitor

Title:

Tankyrase 1 with phthalazinone 1

Structure:

Tankyrase-1. Chain: a, b, c, d. Synonym: tank1,adp-ribosyltransferase diphtheria toxin-like 5,artd5, poly [adp-ribose] polymerase 5a,tnks-1,trf1-interacting ankyrin- related adp-ribose polymerase,tankyrase i. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tnks, parp5a, parpl, tin1, tinf1, tnks1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.20Å R-factor: 0.183 R-free: 0.224

Authors:

S.L.Kazmirski,J.Johannes,J.A.Read,T.Howard,N.A.Larsen,A.D.Ferguson

Key ref:

J.W.Johannes et al. (2015). Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering. Bioorg Med Chem Lett, 25, 5743-5747. PubMed id: 26546219 DOI: 10.1016/j.bmcl.2015.10.079

Date:

20-Oct-15 Release date: 25-Nov-15

Protein chains

O95271  (TNKS1_HUMAN) -  Poly [ADP-ribose] polymerase tankyrase-1 from Homo sapiens

Seq: 1327 a.a.

Struc: 208 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.4.2.- - ?????
• Enzyme class 2: E.C.2.4.2.30 - NAD(+) ADP-ribosyltransferase.

Pathway:

• Reaction: NAD⁺ + (ADP-D-ribosyl)n-acceptor = nicotinamide + (ADP-D- ribosyl)n+1-acceptor + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.bmcl.2015.10.079

Bioorg Med Chem Lett 25:5743-5747 (2015)

PubMed id: 26546219

Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering.

J.W.Johannes, L.Almeida, K.Daly, A.D.Ferguson, S.E.Grosskurth, H.Guan, T.Howard, S.Ioannidis, S.Kazmirski, M.L.Lamb, N.A.Larsen, P.D.Lyne, K.Mikule, C.Ogoe, B.Peng, P.Petteruti, J.A.Read, N.Su, M.Sylvester, S.Throner, W.Wang, X.Wang, J.Wu, Q.Ye, Y.Yu, X.Zheng, D.A.Scott.

ABSTRACT

The propensity for cancer cells to accumulate additional centrosomes relative to normal cells could be exploited for therapeutic benefit in oncology. Following literature reports that suggested TNKS1 (tankyrase 1) and PARP16 may be involved with spindle structure and function and may play a role in suppressing multi-polar spindle formation in cells with supernumerary centrosomes, we initiated a phenotypic screen to look for small molecule poly (ADP-ribose) polymerase (PARP) enzyme family inhibitors that could produce a multi-polar spindle phenotype via declustering of centrosomes. Screening of AstraZeneca's collection of phthalazinone PARP inhibitors in HeLa cells using high-content screening techniques identified several compounds that produced a multi-polar spindle phenotype at low nanomolar concentrations. Characterization of these compounds across a broad panel of PARP family enzyme assays indicated that they had activity against several PARP family enzymes, including PARP1, 2, 3, 5a, 5b, and 6. Further optimization of these initial hits for improved declustering potency, solubility, permeability, and oral bioavailability resulted in AZ0108, a PARP1, 2, 6 inhibitor that potently inhibits centrosome clustering and is suitable for in vivo efficacy and tolerability studies.