PDBsum entry 6t3b

Transferase

PDB id: 6t3b

Contents

Protein chain

804 a.a.

Ligands

M9T

PDB id:

6t3b

Name:

Transferase

Title:

Crystal structure of pi3kgamma with a dihydropurinone inhibitor (compound 4)

Structure:

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform. Chain: a. Fragment: amino acids 144-1102. Synonym: ptdins-3-kinase subunit gamma,phosphatidylinositol 4,5- bisphosphate 3-kinase 110 kda catalytic subunit gamma,p110gamma, phosphoinositide-3-kinase catalytic gamma polypeptide, serine/threonine protein kinase pik3cg,p120-pi3k. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3cg. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.

Resolution:

3.01Å R-factor: 0.231 R-free: 0.274

Authors:

J.Petersen,L.Oster,M.Schimpl,F.W.Goldberg,M.R.V.Finlay,A.K.T.Ting, D.Beattie,G.M.Lamont,C.Fallan,G.L.Wrigley,M.R.Howard,B.Williamson, B.R.Davies,E.B.Cadogan,A.Ramos-Montoya,E.Dean

Key ref:

F.W.Goldberg et al. (2020). The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor. J Med Chem, 63, 3461-3471. PubMed id: 31851518 DOI: 10.1021/acs.jmedchem.9b01684

Date:

10-Oct-19 Release date: 01-Jan-20

Protein chain

P48736  (PK3CG_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform from Homo sapiens

Seq: 1102 a.a.

Struc: 804 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 3: E.C.2.7.1.137 - phosphatidylinositol 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl- sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H⁺
• Enzyme class 4: E.C.2.7.1.153 - phosphatidylinositol-4,5-bisphosphate 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- trisphosphate) + ADP + H⁺
• Enzyme class 5: E.C.2.7.1.154 - phosphatidylinositol-4-phosphate 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + ADP + 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

reference

DOI no: 10.1021/acs.jmedchem.9b01684

J Med Chem 63:3461-3471 (2020)

PubMed id: 31851518

The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor.

F.W.Goldberg, M.R.V.Finlay, A.K.T.Ting, D.Beattie, G.M.Lamont, C.Fallan, G.L.Wrigley, M.Schimpl, M.R.Howard, B.Williamson, M.Vazquez-Chantada, D.G.Barratt, B.R.Davies, E.B.Cadogan, A.Ramos-Montoya, E.Dean.

ABSTRACT

DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound 1. Optimization focused on further improving selectivity while improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound 16 (AZD7648). Compound 16 had no significant off-target activity in the protein kinome and only weak activity versus PI3Kα/γ lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).