6T3B

Crystal structure of PI3Kgamma with a dihydropurinone inhibitor (compound 4)

Summary for 6T3B

• Entry DOI: 10.2210/pdb6t3b/pdb
• Related: 6T3C
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 2-[(4-methoxy-2-methyl-phenyl)amino]-7-methyl-9-(4-oxidanylcyclohexyl)purin-8-one (2 entities in total)
• Functional Keywords: kinase fold, pi3 kinase, type i kinase inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 111110.55

Authors

Petersen, J.,Oster, L.,Schimpl, M.,Goldberg, F.W.,Finlay, M.R.V.,Ting, A.K.T.,Beattie, D.,Lamont, G.M.,Fallan, C.,Wrigley, G.L.,Howard, M.R.,Williamson, B.,Davies, B.R.,Cadogan, E.B.,Ramos-Montoya, A.,Dean, E. (deposition date: 2019-10-10, release date: 2020-01-01, Last modification date: 2024-05-01)

Primary citation

Goldberg, F.W.,Finlay, M.R.V.,Ting, A.K.T.,Beattie, D.,Lamont, G.M.,Fallan, C.,Wrigley, G.L.,Schimpl, M.,Howard, M.R.,Williamson, B.,Vazquez-Chantada, M.,Barratt, D.G.,Davies, B.R.,Cadogan, E.B.,Ramos-Montoya, A.,Dean, E.
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, 2020

PubMed 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 . Optimization focused on further improving selectivity while improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound (AZD7648). Compound 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).

PubMed: 31851518
DOI: 10.1021/acs.jmedchem.9b01684

Experimental method

X-RAY DIFFRACTION (3.01 Å)