Goldberg, Frederick W.; Finlay, M. Raymond V.; Ting, Attilla K. T.; Beattie, David; Lamont, Gillian M.; Fallan, Charlene; Wrigley, Gail L.; Schimpl, Marianne; Howard, Martin R.; Williamson, Beth; Vazquez-Chantada, Mercedes; Barratt, Derek G.; Davies, Barry R.; Cadogan, Elaine B.; Ramos-Montoya, Antonio; Dean, Emma published the artcile< 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>, Recommanded Product: 6-Amino-3-nitro-2-picoline, the main research area is AZD7648 preparation DNA protein kinase inhibitor cancer.
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 vs. 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 phys. 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 vs. 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 clin. studies (NCT03907969).
Journal of Medicinal Chemistry published new progress about Antitumor agents (potential as). 22280-62-2 belongs to class pyridine-derivatives, and the molecular formula is C6H7N3O2, Recommanded Product: 6-Amino-3-nitro-2-picoline.