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

  • J Med Chem. 2018 Nov 21;61(22):9889-9907. doi: 10.1021/acs.jmedchem.8b01187.
Kevin M Foote  1 ,  J Willem M Nissink  1 ,  Thomas McGuire  1 ,  Paul Turner  1 ,  Sylvie Guichard  2 ,  James W T Yates  3 ,  Alan Lau  2 ,  Kevin Blades  1 ,  Dan Heathcote  4 ,  Rajesh Odedra  2 ,  Gary Wilkinson  1 ,  Zena Wilson  2 ,  Christine M Wood  1 ,  Philip J Jewsbury  1
Affiliations
  • 1. Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
  • 2. Bioscience, Oncology, IMED Biotech Unit , AstraZeneca , Chesterford Research Park , Little Chesterford, Cambridge CB10 1XL , U.K.
  • 3. DMPK, Oncology, IMED Biotech Unit , AstraZeneca , Chesterford Research Park , Little Chesterford, Cambridge CB10 1XL , U.K.
  • 4. Discovery Sciences, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
PMID: 30346772 DOI: 10.1021/acs.jmedchem.8b01187
Abstract

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.

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