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PDBsum entry 6t3b
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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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.
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Ref.
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J Med Chem, 2020,
63,
3461-3471.
[DOI no: ]
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PubMed id
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Abstract
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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).
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