Discovery of Orally Bioavailable Purine-Based Inhibitors of the Low-Molecular-Weight Protein Tyrosine Phosphatase

被引：12

作者：

Stanford, Stephanie M. ^{[1
]}

Diaz, Michael A. ^{[1
]}

Ardecky, Robert J. ^{[2
]}

Zou, Jiwen ^{[2
]}

Roosild, Tarmo ^{[2
]}

Holmes, Zachary J. ^{[1
]}

Nguyen, Tiffany P. ^{[1
]}

Hedrick, Michael P. ^{[2
]}

Rodiles, Socorro ^{[2
]}

Guan, April ^{[2
]}

Grotegut, Stefan ^{[2
]}

Santelli, Eugenio ^{[1
]}

Chung, Thomas D. Y. ^{[2
]}

Jackson, Michael R. ^{[2
]}

Bottini, Nunzio ^{[1
]}

Pinkerton, Anthony B. ^{[2
]}

机构：

[1] Univ Calif San Diego, Dept Med, La Jolla, CA 92037 USA

[2] Sanford Burnham Prebys Med Discovery Inst, Conrad Prebys Ctr Chem Genom, La Jolla, CA 92037 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 09期

基金：

美国国家卫生研究院;

关键词：

ACID-PHOSPHATASE; GENOTYPE; GLUCOSE;

D O I：

10.1021/acs.jmedchem.0c02126

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Obesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine phosphatases that negatively regulate insulin receptor signaling. The low-molecular-weight protein tyrosine phosphatase (LMPTP) acts as a critical promoter of insulin resistance in obesity by inhibiting phosphorylation of the liver insulin receptor activation motif. Here, we report development of a novel purine-based chemical series of LMPTP inhibitors. These compounds inhibit LMPTP with an uncompetitive mechanism and are highly selective for LMPTP over other protein tyrosine phosphatases. We also report the generation of a highly orally bioavailable purine-based analogue that reverses obesity-induced diabetes in mice.

引用

页码：5645 / 5653

页数：9

共 36 条

[1] Protein tyrosine phosphatases in the human genome [J].

Alonso, A ;

Sasin, J ;

Bottini, N ;

Friedberg, I ;

Osterman, A ;

Godzik, A ;

Hunter, T ;

Dixon, J ;

Mustelin, T .

CELL, 2004, 117 (06) :699-711

[2]

Alonso A, 2016, METHODS MOL BIOL, V1447, P1, DOI 10.1007/978-1-4939-3746-2_1

[3]

Ardecky R., 2010, Probe Reports from the NIH Molecular Libraries Program

[4]

Bottini N, 2002, ARCH IMMUNOL THER EX, V50, P95

[5] Type 2 diabetes and the genetics of signal transduction: A study of interaction between adenosine deaminase and acid phosphatase locus 1 polymorphisms [J].

Bottini, N ;

Gloria-Bottini, F ;

Borgiani, P ;

Antonacci, E ;

Lucarelli, P ;

Bottini, E .

METABOLISM-CLINICAL AND EXPERIMENTAL, 2004, 53 (08) :995-1001

[6] Insulin Receptor Signaling in Normal and Insulin-Resistant States [J].

Boucher, Jeremie ;

Kleinridders, Andre ;

Kahn, C. Ronald .

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2014, 6 (01)

[7] Low molecular weight protein tyrosine phosphatase: Multifaceted functions of an evolutionarily conserved enzyme [J].

Caselli, Anna ;

Paoli, Paolo ;

Santi, Alice ;

Mugnaioni, Camilla ;

Toti, Alessandra ;

Camici, Guido ;

Cirri, Paolo .

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 2016, 1864 (10) :1339-1355

[8] Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery [J].

Coussens, Nathan P. ;

Sittampalam, G. Sitta ;

Guha, Rajarshi ;

Brimacombe, Kyle ;

Grossman, Abigail ;

Chung, Thomas D. Y. ;

Weidner, Jeffrey R. ;

Riss, Terry ;

Trask, O. Joseph ;

Auld, Douglas ;

Dahlin, Jayme L. ;

Devanaryan, Viswanath ;

Foley, Timothy L. ;

Mcgee, James ;

Kahl, Steven D. ;

Kales, Stephen C. ;

Arkin, Michelle ;

Baell, Jonathan ;

Bejcek, Bruce ;

Gal-Edd, Neely ;

Glicksman, Marcie ;

Haas, Joseph V. ;

Iversen, Philip W. ;

Hoeppner, Marilu ;

Lathrop, Stacy ;

Sayers, Eric ;

Liu, Hanguan ;

Trawick, Bart ;

Mcvey, Julie ;

Lemmon, Vance P. ;

Li, Zhuyin ;

McManus, Owen ;

Minor, Lisa ;

Napper, Andrew ;

Wildey, Mary Jo ;

Pacifici, Robert ;

Chin, William W. ;

Xia, Menghang ;

Xu, Xin ;

Lal-Nag, Madhu ;

Hall, Matthew D. ;

Michael, Sam ;

Inglese, James ;

Simeonov, Anton ;

Austin, Christopher P. .

CTS-CLINICAL AND TRANSLATIONAL SCIENCE, 2018, 11 (05) :461-470

[9] Features and development of Coot [J].

Emsley, P. ;

Lohkamp, B. ;

Scott, W. G. ;

Cowtan, K. .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 2010, 66 :486-501

[10] Phosphotyrosine protein phosphatases and diabetic pregnancy: An association between low molecular weight acid phosphatase and degree of glycemic control [J].

GloriaBottini, F ;

Gerlini, G ;

Lucarini, N ;

Borgiani, P ;

Amante, A ;

LaTorre, M ;

Antonacci, E ;

Bottini, E .

EXPERIENTIA, 1996, 52 (04) :340-343

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