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

Frederick W Goldberg; M Raymond V Finlay; Attilla K T Ting; David Beattie; Gillian M Lamont; Charlene Fallan; Gail L Wrigley; Marianne Schimpl; Martin R Howard; Beth Williamson; Mercedes Vazquez-Chantada; Derek G Barratt; Barry R Davies; Elaine B Cadogan; Antonio Ramos-Montoya; Emma Dean

doi:10.1021/acs.jmedchem.9b01684

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

J Med Chem. 2020 Apr 9;63(7):3461-3471. doi: 10.1021/acs.jmedchem.9b01684. Epub 2020 Jan 15.

Authors

Frederick W Goldberg¹, M Raymond V Finlay¹, Attilla K T Ting¹, David Beattie¹, Gillian M Lamont¹, Charlene Fallan¹, Gail L Wrigley¹, Marianne Schimpl², Martin R Howard¹, Beth Williamson¹, Mercedes Vazquez-Chantada², Derek G Barratt², Barry R Davies¹, Elaine B Cadogan¹, Antonio Ramos-Montoya¹, Emma Dean¹

Affiliations

¹ Oncology R&D, AstraZeneca, Cambridge CB4 0FZ, U.K.
² Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0FZ, U.K.

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

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).

Publication types

News

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Class Ib Phosphatidylinositol 3-Kinase / metabolism
DNA-Activated Protein Kinase / antagonists & inhibitors*
Dogs
Drug Discovery
Humans
Mice
Molecular Structure
Neoplasms / drug therapy
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use*
Purines / chemical synthesis
Purines / pharmacokinetics
Purines / therapeutic use*
Pyrans / chemical synthesis
Pyrans / pharmacokinetics
Pyrans / therapeutic use*
Rats
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / pharmacokinetics
Triazoles / therapeutic use*
Xenograft Model Antitumor Assays

Substances

AZD7648
Antineoplastic Agents
Protein Kinase Inhibitors
Purines
Pyrans
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
Triazoles
Class Ib Phosphatidylinositol 3-Kinase
DNA-Activated Protein Kinase

Associated data

ClinicalTrials.gov/NCT03907969