Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent

The
kinase ataxia telangiectasia mutated and rad3 related (ATR)
is a key regulator of the DNA-damage response and the apical kinase
which orchestrates the cellular processes that repair stalled replication
forks (replication stress) and associated DNA double-strand breaks.
Inhibition of repair pathways mediated by ATR in a context where alternative
pathways are less active is expected to aid clinical response by increasing
replication stress. Here we describe the development of the clinical
candidate 2 (AZD6738), a potent and selective sulfoximine
morpholino­pyrimidine ATR inhibitor with excellent preclinical
physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating
CYP3A4 time-dependent inhibition starting from the earlier described
inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and
achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials
as an anticancer agent.