Novel PTP1B inhibitors identified by DNA display of fragment pairs

被引：35

作者：

Barluenga, Sofia ^{[1
]}

Zambaldo, Claudio ^{[1
]}

Ioannidou, Heraklidia A. ^{[2
]}

Ciobanu, Mihai ^{[3
]}

Morieux, Pierre ^{[4
]}

Daguer, Jean-Pierre ^{[1
]}

Winssinger, Nicolas ^{[1
]}

机构：

[1] Univ Geneva, NCCR Chem Biol, Dept Organ Chem, CH-1211 Geneva 4, Switzerland

[2] Univ Nicosia, Dept Life & Hlth Sci, Nicosia, Cyprus

[3] Lonza AG, Visp, Switzerland

[4] PerkinElmer SAS, Villebon Sur Yvette, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 03期

基金：

瑞士国家科学基金会;

关键词：

DNA-encoded library; Peptide nucleic acid (PNA); Fragment based drug discovery; PTP1B; TYROSINE-PHOSPHATASE; 1B; PEPTIDE NUCLEIC-ACID; ENCODED SYNTHESIS PES; PNA; LIBRARIES; SELECTION; DISCOVERY; LIGANDS; MOLECULES; CYSTEINE;

D O I：

10.1016/j.bmcl.2015.11.102

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

DNA display of PNA-encoded libraries was used to pair fragments containing different phosphotyrosine surrogates with diverse triazoles. Microarray-based screening of the combinatorially paired fragment sets (62,500 combinations) against a prototypical phosphatase, PTP1B, was used to identify the fittest fragments. A focused library (10,000 members) covalently pairing identified fragments with linkers of different length and geometry was synthesized. Screening of the focused library against PTP1B and closely related TCPTP revealed orthogonal inhibitors. The selectivity of the identified inhibitors for PTP1B versus TCPT was confirmed by enzymatic inhibition assay. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：1080 / 1085

页数：6

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