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

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

Kevin M Foote, J Willem M Nissink, Thomas McGuire, Paul Turner, Sylvie Guichard, James W T Yates, Alan Lau, Kevin Blades, Dan Heathcote, Rajesh Odedra, Gary Wilkinson, Zena Wilson, Christine M Wood, Philip J Jewsbury

J Med Chem. 2018 Nov 21;61(22):9889-9907.

PMID: 30346772

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1233339224	AZ20		1233339-22-4	Price

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