Targeted Degradation of the Oncogenic Phosphatase SHP2,Biochemistry

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Targeted Degradation of the Oncogenic Phosphatase SHP2
Biochemistry ( IF 2.9 ) Pub Date : 2021-08-19 , DOI: 10.1021/acs.biochem.1c00377
Vidyasiri Vemulapalli _{1,

2} , Katherine A Donovan ₂ , Tom C M Seegar ₃ , Julia M Rogers ₁ , Munhyung Bae ₁ , Ryan J Lumpkin ₂ , Ruili Cao ₁ , Matthew T Henke ₁ , Soumya S Ray ₄ , Eric S Fischer _{1,

2} , Gregory D Cuny ₅ , Stephen C Blacklow _{1,

2}

Affiliation

SHP2 is a protein tyrosine phosphatase that plays a critical role in the full activation of the Ras-MAPK pathway upon stimulation of receptor tyrosine kinases, which are frequently amplified or mutationally activated in human cancer. In addition, activating mutations in SHP2 result in developmental disorders and hematologic malignancies. Several allosteric inhibitors have been developed for SHP2 and are currently in clinical trials. Here, we report the development and evaluation of a SHP2 PROTAC created by conjugating RMC-4550 with pomalidomide using a PEG linker. This molecule is highly selective for SHP2, induces degradation of SHP2 in leukemic cells at submicromolar concentrations, inhibits MAPK signaling, and suppresses cancer cell growth. SHP2 PROTACs serve as an alternative strategy for targeting ERK-dependent cancers and are useful tools alongside allosteric inhibitors for dissecting the mechanisms by which SHP2 exerts its oncogenic activity.

中文翻译：

致癌磷酸酶 SHP2 的靶向降解

SHP2 是一种蛋白质酪氨酸磷酸酶，在受体酪氨酸激酶刺激后，在 Ras-MAPK 通路的完全激活中起关键作用，受体酪氨酸激酶在人类癌症中经常被放大或突变激活。此外，SHP2 中的激活突变会导致发育障碍和血液系统恶性肿瘤。已经为 SHP2 开发了几种变构抑制剂，目前正在临床试验中。在这里，我们报告了通过使用 PEG 接头将 RMC-4550 与泊马度胺结合而创建的 SHP2 PROTAC 的开发和评估。该分子对 SHP2 具有高度选择性，在亚微摩尔浓度下诱导白血病细胞中 SHP2 的降解，抑制 MAPK 信号传导，并抑制癌细胞生长。

更新日期：2021-08-31

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