Development of a Series of Pyrrolopyridone MAT2A Inhibitors

被引：5

作者：

Atkinson, Stephen J. ^{[1
]}

Bagal, Sharan K. ^{[1
]}

Argyrou, Argyrides ^{[1
,5
]}

Askin, Sean ^{[2
]}

Cheung, Tony ^{[3
]}

Chiarparin, Elisabetta ^{[1
]}

Coen, Muireann ^{[4
]}

Collie, Iain T. ^{[5
]}

Dale, Ian L. ^{[5
]}

De Fusco, Claudia ^{[5
]}

Dillman, Keith ^{[3
]}

Evans, Laura ^{[1
]}

Feron, Lyman J. ^{[1
]}

Foster, Alison J. ^{[4
]}

Grondine, Michael ^{[3
]}

Kantae, Vasudev ^{[5
]}

Lamont, Gillian M. ^{[1
]}

Lamont, Scott ^{[1
]}

Lynch, James T. ^{[1
]}

Lill, Sten Nilsson ^{[4
]}

Robb, Graeme R. ^{[1
]}

Saeh, Jamal ^{[3
]}

Schimpl, Marianne ^{[5
]}

Scott, James S. ^{[1
]}

Smith, James ^{[1
]}

Srinivasan, Bharath ^{[5
]}

Tentarelli, Sharon ^{[3
]}

Vazquez-Chantada, Mercedes ^{[5
]}

Wagner, David ^{[1
]}

Walsh, Jarrod J. ^{[5
]}

Watson, David ^{[1
]}

Williamson, Beth ^{[1
]}

机构：

[1] AstraZeneca, Discovery Ctr, Oncol R&D, Cambridge CB2 0AA, England

[2] AstraZeneca, Adv Drug Delivery, Pharmaceut Sci,R&D, Cambridge CB2 0AA, England

[3] AstraZeneca, Oncol R&D, R&D Boston, Waltham, MA 02451 USA

[4] Discovery Ctr, Clin Pharmacol & Safety Sci, R&D, AstraZeneca, Cambridge CB2 0AA, England

[5] Discovery Ctr, Discovery Sci R&D, AstraZeneca, Cambridge CB2 0AA, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 06期

关键词：

S-ADENOSYLMETHIONINE; FREE-ENERGY; MTAP; METHIONINE; DISCOVERY;

D O I：

10.1021/acs.jmedchem.3c01860

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

引用

页码：4541 / 4559

页数：19

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