Targeted Degradation of the Oncogenic Phosphatase SHP2.
Vidyasiri Vemulapalli,Katherine A. Donovan,Tom C. M. Seegar,Julia M. Rogers,Munhyung Bae,Ryan J. Lumpkin,Ruili Cao,Matthew T. Henke,Soumya S. Ray,Eric S. Fischer,Gregory D. Cuny,Stephen C. Blacklow +11 more
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TLDR
In this paper, a SHP2 PROTAC was developed by conjugating RMC-4550 with pomalidomide using a PEG linker, which was shown to be highly selective for SHP 2 in leukemic cells at submicromolar concentrations, inhibits MAPK signaling and suppresses cancer cell growth.Abstract:
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.read more
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PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)
TL;DR: Proteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years as discussed by the authors , which uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through a ubiquitin-proteasome system.
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Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy.
TL;DR: This Perspective briefly summarizes the strategies targeting SHP2 including inhibitors, activators, and proteolysis-targeting chimera (PROTAC) degraders and highlights the target- and pathway-dependent combination strategies of SHp2 for cancer therapy.
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A comprehensive review of SHP2 and its role in cancer
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Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy
TL;DR: In this article , the authors provide a comprehensive summary of the structure, the double-edged sword function, and extensive signaling pathways of all protein phosphatases in inflammatory-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials.
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Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers.
Soon-Sil Hyun,Dongyun Shin +1 more
TL;DR: In this paper, the authors discuss small-molecule inhibitors, TPD-based small molecule chemicals for targeting RAS pathway proteins, and their potential applications for treating KRAS-mutant cancers.
References
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Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling.
Chen Liu,Hengyu Lu,Hongyun Wang,Alice Loo,Xiamei Zhang,Guizhi Yang,Colleen Kowal,Scott Delach,Ye Wang,Silvia Goldoni,William D. Hastings,Karrie Wong,Hui Gao,Matthew J. Meyer,Susan Moody,Matthew J. LaMarche,Jeffrey A. Engelman,Juliet Williams,Peter S. Hammerman,Tinya Abrams,Morvarid Mohseni,Giordano Caponigro,Huai Xiang Hao +22 more
TL;DR: The findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment.
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Targeted degradation of the enhancer lysine acetyltransferases CBP and p300.
Raghu Vannam,Jan Fehmi Sayılgan,Samuel Ojeda,Barbara Karakyriakou,Eileen Hu,Johannes Kreuzer,Robert Morris,Xcanda Ixchel Herrera Lopez,Sumit Rai,Wilhelm Haas,Michael S. Lawrence,Michael S. Lawrence,Christopher J. Ott,Christopher J. Ott +13 more
TL;DR: In this article, a chemical degrader of p300/CBP, dCBP-1, was proposed to eliminate the enhancer that drives myeloma oncogene expression.
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Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy.
Liguo Wang,Xuejing Shao,Tianbai Zhong,Yue Wu,Aixiao Xu,Xiuyun Sun,Hongying Gao,Yongbo Liu,Tianlong Lan,Yan Tong,Xue Tao,Wenxin Du,Wei Wang,Yingqian Chen,Ting Li,Xianbin Meng,Haiteng Deng,Bo Yang,Qiaojun He,Meidan Ying,Yu Rao,Yu Rao +21 more
TL;DR: Wang et al. as mentioned in this paper developed first-in-class CDK2-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent CDK 2 degradation in different cell lines without comparable degradation of other targets.
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Degradation of target protein in living cells by small-molecule proteolysis inducer
TL;DR: A potentially general method of degrading any targeted proteins by the ubiquitin-dependent proteolysis in living cells, using small-molecule proteolytic inducer (SMPI).
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Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2
Jonathan R. LaRochelle,Michelle Fodor,Xiang Xu,Izabela Durzynska,Lixin Fan,Travis Stams,Ho Man Chan,Matthew J. LaMarche,Rajiv Chopra,Ping Wang,Pascal D. Fortin,Michael G. Acker,Stephen C. Blacklow +12 more
TL;DR: X-ray crystallography, small-angle X-ray scattering, and biochemistry are combined to elucidate structural and mechanistic features of three cancer-associated SHP2 variants harboring single point mutations within the N-SH2:PTP interdomain autoinhibitory interface.