Discovery of a Selective Covalent Inhibitor of Lysophospholipase-like 1 (LYPLAL1) as a Tool to Evaluate the Role of this Serine Hydrolase in Metabolism

被引：18

作者：

Ahn, Kay ^{[1
,4
]}

Boehm, Markus ^{[2
]}

Brown, Matthew F. ^{[2
]}

Calloway, Jessica ^{[1
]}

Che, Ye ^{[2
]}

Chen, Jinshan ^{[2
]}

Fennell, Kimberly F. ^{[2
]}

Geoghegan, Kieran F. ^{[2
]}

Gilbert, Adam M. ^{[2
]}

Gutierrez, Jemy A. ^{[1
]}

Kalgutkar, Amit S. ^{[3
]}

Lanba, Adhiraj ^{[1
]}

Limberalds, Chris ^{[2
]}

Magee, Thomas V. ^{[2
]}

O'Doherty, Inish ^{[1
]}

Oliver, Robert ^{[2
]}

Pabst, Brandon ^{[1
]}

Pandit, Jayvardhan ^{[2
]}

Parris, Kevin ^{[2
]}

Pfefferkorn, Jeffrey A. ^{[1
]}

Rolph, Timothy P. ^{[1
]}

Patel, Rushi ^{[1
]}

Schuff, Brandon ^{[2
]}

Shanmugasundaram, Veerabahu ^{[2
]}

Starr, Jeremy T. ^{[2
]}

Varghese, Alison H. ^{[2
]}

Vera, Nicholas B. ^{[1
]}

Vernochet, Cecile ^{[1
]}

Yan, Jiangli ^{[2
]}

机构：

[1] Pfizer Inc, Cardiovasc Metab & Endocrine Dis CVMED Res Unit, 610 Main St, Cambridge, MA 02139 USA

[2] Pfizer Inc, Worldwide Med Chem, Eastern Point Rd, Groton, CT 06340 USA

[3] Pfizer Inc, Pharmacokinet Dynam & Metab, Eastern Point Rd, Groton, CT 06340 USA

[4] Janssen Res & Dev, 1400 McKean Rd, Spring House, PA 19477 USA

来源：

ACS CHEMICAL BIOLOGY | 2016年 / 11卷 / 09期

关键词：

PIPERIDYL-1,2,3-TRIAZOLE UREAS; CHEMICAL PROBES; OBESITY; OPTIMIZATION; LIPASE; POTENT; ABHD6;

D O I：

10.1021/acschembio.6b00266

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Lysophospholipase-like 1 (LYPLAL1) is an uncharacterized metabolic serine hydrolase. Human genome-wide association studies link variants of the gene encoding this enzyme to fat distribution, waist-to-hip ratio, and nonalcoholic fatty liver disease. We describe the discovery of potent and selective covalent small-molecule inhibitors of LYPLAL1 and their use to investigate its role in hepatic metabolism. In hepatocytes, selective inhibition of LYPLAL1 increased glucose production supporting the inference that LYPLAL1 is a significant actor in hepatic metabolism. The results provide an example of how a selective chemical tool can contribute to evaluating a hypothetical target for therapeutic intervention, even in the absence of complete biochemical characterization.

引用

页码：2529 / 2540

页数：12

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