Discovery of AZD4625, a Covalent Allosteric Inhibitor of the MutantGTPase KRASG12C

被引：40

作者：

Kettle, Jason G. ^{[1
]}

Bagal, Sharan K. ^{[1
]}

Bickerton, Sue ^{[1
]}

Bodnarchuk, Michael S. ^{[1
]}

Boyd, Scott ^{[1
]}

Breed, Jason ^{[1
]}

Carbajo, Rodrigo J. ^{[1
]}

Cassar, Doyle J. ^{[1
]}

Chakraborty, Atanu ^{[1
]}

Cosulich, Sabina ^{[1
]}

Cumming, Iain ^{[1
]}

Davies, Michael ^{[1
]}

Davies, Nichola L. ^{[1
]}

Eatherton, Andrew ^{[1
]}

Evans, Laura ^{[1
]}

Feron, Lyman ^{[1
]}

Fillery, Shaun ^{[1
]}

Gleave, Emma S. ^{[1
]}

Goldberg, Frederick W. ^{[1
]}

Hanson, Lyndsey ^{[2
]}

Harlfinger, Stephanie ^{[1
]}

Howard, Martin ^{[1
]}

Howells, Rachel ^{[1
]}

Jackson, Anne ^{[1
]}

Kemmitt, Paul ^{[1
]}

Lamont, Gillian ^{[1
]}

Lamont, Scott ^{[1
]}

Lewis, Hilary J. ^{[1
]}

Liu, Libin ^{[3
]}

Niedbala, Michael J. ^{[4
]}

Phillips, Christopher ^{[1
]}

Polanski, Radek ^{[1
]}

Raubo, Piotr ^{[1
]}

Robb, Graeme ^{[1
]}

Robinson, David M. ^{[1
]}

Ross, Sarah ^{[1
]}

Sanders, Matthew G. ^{[1
]}

Tonge, Michael ^{[1
]}

Whiteley, Rebecca ^{[1
]}

Wilkinson, Stephen ^{[1
]}

Yang, Junsheng ^{[3
]}

Zhang, Wenman ^{[3
]}

机构：

[1] AstraZeneca, Oncol R&D, Cambridge CB4 0WG, England

[2] AstraZeneca, Oncol R&D, Alderley Pk SK10 4TG, England

[3] Pharmaron Beijing Co Ltd, Beijing 100176, Peoples R China

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 09期

关键词：

LUNG ADENOCARCINOMAS; FREE-ENERGIES; WATER;

D O I：

10.1021/acs.jmedchem.2c00369

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

KRAS is an archetypal high-value intractableoncology drug target. The glycine to cysteine mutation at codon12 represents an Achilles heel that has now rendered thisimportant GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of21,AZD4625, a clinical development candidate for the treatment ofKRASG12Cpositive tumors. Highlights include a quinazolinetethering strategy to lock out a bio-relevant binding conformationand an optimization strategy focused on the reduction ofextrahepatic clearance mechanisms seen in preclinical species.Crystallographic analysis was also key in helping to rationalizeunusual structure-activity relationship in terms of ring size andenantio-preference. AZD4625 is a highly potent and selectiveinhibitor of KRASG12Cwith an anticipated low clearance and high oral bioavailability profile in humans

引用

页码：6940 / 6952

页数：13

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