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首页> 外文期刊>Bulletin of the Chemical Society of Japan >Identification of a Novel SHP-2 Protein Tyrosine Phosphatase Inhibitor
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Identification of a Novel SHP-2 Protein Tyrosine Phosphatase Inhibitor

机译：新型SHP-2蛋白酪氨酸磷酸酶抑制剂的鉴定

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摘要

The Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) is a nonreceptor protein tyrosine phosphatase (PTP) involved in extracellular-regulated kinase (ERK) activation. Recent studies have shown that gain-of-function mutations in SHP-2 are associated with several diseases, including LEOPARD syndrome, Noonan syndrome, and juvenile myelomonocytic leukemia. In this study, we identified the novel SHP-2 inhibitor 3-(1-benzimidazolylmethyl)-6-p-tolyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (MLS-001). SHIP-2 activity was inhibited by MLS-001, whereas other types of PTPs, namely ACP1, CDC25A, DUSP3, DUSP14, DUSP18, DUSP22, DUSP23, DUSP26, and SSH3, were not. Furthermore, TCPTP and SHP-1 that are closely related to SHP-2 were not inhibited by the inhibitor. Kinetic studies with MLS-001 and SHP-2 revealed a competitive inhibition. The SHP-2 expressing cells treated with MLS-001 demonstrated reduced SHP-2 phosphatase activity, thereby suggesting that MLS-001 effectively passes through cell membranes. In addition, MLS-001 reduced SHP-2-mediated phosphorylation in the activation loop of ERK in cells. Therefore, MLS-001 could be a lead compound for developing a potent SHP-2 inhibitor.
机译：SRC同源性2（SH2）含有结构域的磷酸酶2（SHP-2）是参与细胞外调节激酶（ERK）活化的非接受蛋白酪氨酸磷酸酶（PTP）。最近的研究表明，SHP-2中的功能性突变与几种疾病有关，包括豹综合征，非洲综合征和青少年骨髓细胞白血病。在这项研究中，我们鉴定了新的SHP-2抑制剂3-（1-苯并咪唑基甲基）-6-P-甲苯基 - [1,2,4]三唑唑[3,4-B] [1,3,4]噻二唑（ MLS-001）。通过MLS-001抑制船舶2活性，而其他类型的PTP，即ACP1，CDC25A，DUSP3，DUSP14，DUSP18，DUSP22，DUSP23，DUSP26和SSH3则不是。此外，抑制剂不抑制与SHP-2密切相关的TCPTP和SHP-1。 MLS-001和SHP-2的动力学研究显示出具有竞争性抑制作用。用MLS-001处理的SHP-2表达细胞证明了SHP-2磷酸酶活性降低，从而表明MLS-001有效地通过细胞膜。另外，MLS-001在电池中ERK的活化环中减少了SHP-2介导的磷酸化。因此，MLS-001可以是用于开发有效的SHP-2抑制剂的铅化合物。

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    Ju Anna; Seo Huiyun; Kim Heemun; Park Byoung Chul; Park Sung Goo; Kim Jeong Hoon; Choi Hyung-Kyoon; Min Kyung Hoon; Cho Sayeon;

  • 作者单位

    Chung Ang Univ Coll Pharm Seoul 156756 South Korea;

    Chung Ang Univ Coll Pharm Seoul 156756 South Korea;

    Chung Ang Univ Coll Pharm Seoul 156756 South Korea;

    Korea Res Inst Biosci &

    Biotechnol Med Prote Res Ctr Taejon 305333 South Korea;

    Korea Res Inst Biosci &

    Biotechnol Med Prote Res Ctr Taejon 305333 South Korea;

    Korea Res Inst Biosci &

    Biotechnol Med Prote Res Ctr Taejon 305333 South Korea;

    Chung Ang Univ Coll Pharm Seoul 156756 South Korea;

    Chung Ang Univ Coll Pharm Seoul 156756 South Korea;

    Chung Ang Univ Coll Pharm Seoul 156756 South Korea;

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  • 正文语种 eng
  • 中图分类 化学;
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