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：17

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

共 22 条

[1] Adibekian A, 2011, NAT CHEM BIOL, V7, P469, DOI [10.1038/NCHEMBIO.579, 10.1038/nchembio.579]
[2] The promise and peril of chemical probes
Arrowsmith, Cheryl H.
Audia, James E.
Austin, Christopher
Baell, Jonathan
Bennett, Jonathan
Blagg, Julian
Bountra, Chas
Brennan, Paul E.
Brown, Peter J.
Bunnage, Mark E.
Buser-Doepner, Carolyn
Campbell, Robert M.
Carter, Adrian J.
Cohen, Philip
Copeland, Robert A.
Cravatt, Ben
Dahlin, Jayme L.
Dhanak, Dashyant
Edwards, Aled M.
Frye, Stephen V.
Gray, Nathanael
Grimshaw, Charles E.
Hepworth, David
Howe, Trevor
Huber, Kilian V. M.
Jin, Jian
Knapp, Stefan
Kotz, Joanne D.
Kruger, Ryan G.
Lowe, Derek
Mader, Mary M.
Marsden, Brian
Mueller-Fahrnow, Anke
Mueller, Susanne
O'Hagan, Ronan C.
Overington, John P.
Owen, Dafydd R.
Rosenberg, Saul H.
Roth, Brian
Ross, Ruth
Schapira, Matthieu
Schreiber, Stuart L.
Shoichet, Brian
Sundstrom, Michael
Superti-Furga, Giulio
Taunton, Jack
Toledo-Sherman, Leticia
Walpole, Chris
Walters, Michael A.
Willson, Timothy M.
[J]. NATURE CHEMICAL BIOLOGY, 2015, 11 (08) : 536 - 541
[3] The pharmacological landscape and therapeutic potential of serine hydrolases
Bachovchin, Daniel A.
Cravatt, Benjamin F.
[J]. NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (01) : 52 - 68
[4] Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors
Bachovchin, Daniel A.
Mohr, Justin T.
Speers, Anna E.
Wang, Chu
Berlin, Jacob M.
Spicer, Timothy P.
Fernandez-Vega, Virneliz
Chase, Peter
Hodder, Peter S.
Schuerer, Stephan C.
Nomura, Daniel K.
Rosen, Hugh
Fu, Gregory C.
Cravatt, Benjamin F.
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (17) : 6811 - 6816
[5] Implications of Central Obesity-Related Variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on Quantitative Metabolic Traits in Adult Danes
Bille, Dorthe S.
Banasik, Karina
Justesen, Johanne M.
Sandholt, Camilla H.
Sandbaek, Annelli
Lauritzen, Torsten
Jorgensen, Torben
Witte, Daniel R.
Holm, Jens-Christian
Hansen, Torben
Pedersen, Oluf
[J]. PLOS ONE, 2011, 6 (06):
[6] Crystal structure of the predicted phospholipase LYPLAL1 reveals unexpected functional plasticity despite close relationship to acyl protein thioesterases
Buerger, Marco
Zimmermann, Tobias J.
Kondoh, Yasumitsu
Stege, Patricia
Watanabe, Nobumoto
Osada, Hiroyuki
Waldmann, Herbert
Vetter, Ingrid R.
[J]. JOURNAL OF LIPID RESEARCH, 2012, 53 (01) : 43 - 50
[7] Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma
Chambers, John C.
Zhang, Weihua
Sehmi, Joban
Li, Xinzhong
Wass, Mark N.
Van der Harst, Pim
Holm, Hilma
Sanna, Serena
Kavousi, Maryam
Baumeister, Sebastian E.
Coin, Lachlan J.
Deng, Guohong
Gieger, Christian
Heard-Costa, Nancy L.
Hottenga, Jouke-Jan
Kuehnel, Brigitte
Kumar, Vinod
Lagou, Vasiliki
Liang, Liming
Luan, Jian'an
Vidal, Pedro Marques
Leach, Irene Mateo
O'Reilly, Paul F.
Peden, John F.
Rahmioglu, Nilufer
Soininen, Pasi
Speliotes, Elizabeth K.
Yuan, Xin
Thorleifsson, Gudmar
Alizadeh, Behrooz Z.
Atwood, Larry D.
Borecki, Ingrid B.
Brown, Morris J.
Charoen, Pimphen
Cucca, Francesco
Das, Debashish
de Geus, Eco J. C.
Dixon, Anna L.
Doering, Angela
Ehret, Georg
Eyjolfsson, Gudmundur I.
Farrall, Martin
Forouhi, Nita G.
Friedrich, Nele
Goessling, Wolfram
Gudbjartsson, Daniel F.
Harris, Tamara B.
Hartikainen, Anna-Liisa
Heath, Simon
Hirschfield, Gideon M.
[J]. NATURE GENETICS, 2011, 43 (11) : 1131 - 1138
[8] HADVARY P, 1991, J BIOL CHEM, V266, P2021
[9] Development and Optimization of Piperidyl-1,2,3-Triazole Ureas as Selective Chemical Probes of Endocannabinoid Biosynthesis
Hsu, Ku-Lung
Tsuboi, Katsunori
Whitby, Landon R.
Speers, Anna E.
Pugh, Holly
Inloes, Jordon
Cravatt, Benjamin F.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (21) : 8257 - 8269
[10] Discovery and Optimization of Piperidyl-1,2,3-Triazole Ureas as Potent, Selective, and in Vivo-Active Inhibitors of α/β-Hydrolase Domain Containing 6 (ABHD6)
Hsu, Ku-Lung
Tsuboi, Katsunori
Chang, Jae Won
Whitby, Landon R.
Speers, Anna E.
Pugh, Holly
Cravatt, Benjamin F.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (21) : 8270 - 8279

← 1 2 3 →