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

被引：228

作者：

Foote, Kevin M. ^{[1
,5
]}

Nissink, J. Willem M. ^{[1
]}

McGuire, Thomas ^{[1
]}

Turner, Paul ^{[1
]}

Guichard, Sylvie ^{[2
,6
]}

Yates, James W. T. ^{[3
]}

Lau, Alan ^{[2
]}

Blades, Kevin ^{[1
,7
]}

Heathcote, Dan ^{[4
]}

Odedra, Rajesh ^{[2
,8
]}

Wilkinson, Gary ^{[1
,9
]}

Wilson, Zena ^{[2
]}

Wood, Christine M. ^{[1
]}

Jewsbury, Philip J. ^{[1
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Chem, Oncol, Cambridge Sci Pk,310 Milton Rd, Cambridge CB4 0WG, England

[2] AstraZeneca, IMED Biotech Unit, Biosci, Chesterford Res Pk, Cambridge CB10 1XL, England

[3] AstraZeneca, IMED Biotech Unit, Oncol, DMPK, Chesterford Res Pk, Cambridge CB10 1XL, England

[4] AstraZeneca, IMED Biotech Unit, Discovery Sci, Cambridge Sci Pk,310 Milton Rd, Cambridge CB4 0WG, England

[5] Pharmaron, Drug Discovery Serv Europe, Hertford Rd, Hoddesdon EN11 9BU, Herts, England

[6] Forma Therapeut, 500 Arsenal St, Watertown, MA 02472 USA

[7] AMR Ctr Ltd, 19B70,Mereside Alderley Pk, Alderley Edge SK10 4T, England

[8] Evotec, 114 Innovat Dr,Milton Pk, Abingdon OX14 4RZ, Oxon, England

[9] Bayer, Mullerstr 178, D-13353 Berlin, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 22期

关键词：

MECHANISM-BASED INACTIVATION; SELECTIVE INHIBITOR; CYTOCHROME-P450; ENZYMES; SYNTHETIC LETHALITY; SULFOXIMINES; DRUGS; BIOTRANSFORMATION; BIOACTIVATION; PREDICTIONS; PI3K-ALPHA;

D O I：

10.1021/acs.jmedchem.8b01187

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：9889 / 9907

页数：19

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