Journal ArticleDOI
Selective Inhibitors of the Protein Tyrosine Phosphatase Shp2 Block Cellular Motility and Growth of Cancer Cells in Vitro and in Vivo.
Stefanie Grosskopf,Stefanie Grosskopf,Stefanie Grosskopf,Chris Eckert,Chris Eckert,Christoph Arkona,Silke Radetzki,Kerstin Böhm,Udo Heinemann,Gerhard Wolber,Jens-Peter von Kries,Walter Birchmeier,Jörg Rademann,Jörg Rademann +13 more
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TLDR
In cell culture experiments compound 25 was found to block hepatocyte growth factor‐stimulated epithelial–mesenchymal transition of human pancreatic adenocarcinoma (HPAF) cells, and strengthens the hypothesis that SHP2 is a relevant protein target for the inhibition of mobility and invasiveness of cancer cells.Abstract:
Selective inhibitors of the protein tyrosine phosphatase SHP2 (src homology region 2 domain phosphatase; PTPN11), an enzyme that is deregulated in numerous human tumors, were generated through a combination of chemical synthesis and structure-based rational design. Seventy pyridazolon-4-ylidenehydrazinyl benzenesulfonates were prepared and evaluated in enzyme assays. The binding modes of active inhibitors were simulated in silico using a newly generated crystal structure of SHP2. The most powerful compound, GS-493 (4-{(2Z)-2-[1,3-bis(4-nitrophenyl)-5-oxo-1,5-dihydro-4H-pyrazol-4-yliden]hydrazino}benzenesulfonic acid; 25) inhibited SHP2 with an IC50 value of 71±15 nM in the enzyme assay and was 29- and 45-fold more active toward SHP2 than against related SHP1 and PTP1B. In cell culture experiments compound 25 was found to block hepatocyte growth factor (HGF)-stimulated epithelial-mesenchymal transition of human pancreatic adenocarcinoma (HPAF) cells, as indicated by a decrease in the minimum neighbor distances of cells. Moreover, 25 inhibited cell colony formation in the non-small-cell lung cancer cell line LXFA 526L in soft agar. Finally, 25 was observed to inhibit tumor growth in a murine xenograft model. Therefore, the novel specific compound 25 strengthens the hypothesis that SHP2 is a relevant protein target for the inhibition of mobility and invasiveness of cancer cells.read more
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Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases
Ying-Nan P. Chen,Matthew J. LaMarche,Ho Man Chan,Peter Fekkes,Jorge Garcia-Fortanet,Michael G. Acker,Brandon Antonakos,Chen Christine Hiu-Tung,Zhouliang Chen,Vesselina G. Cooke,Jason R. Dobson,Zhan Deng,Feng Fei,Brant Firestone,Michelle Fodor,Cary Fridrich,Hui Gao,Denise Grunenfelder,Huaixiang Hao,Jaison Jacob,Samuel B. Ho,Kathy Hsiao,Zhao B. Kang,Rajesh Karki,Mitsunori Kato,Jay Larrow,Laura R. La Bonte,Francois Lenoir,Gang Liu,Shumei Liu,Dyuti Majumdar,Matthew J. Meyer,Palermo Mark G,Lawrence Blas Perez,Minying Pu,Edmund Price,Christopher Quinn,Subarna Shakya,Michael Shultz,Joanna Slisz,Kavitha Venkatesan,Ping Wang,Markus Warmuth,Sarah Williams,Guizhi Yang,Jing Yuan,Ji-Hu Zhang,Ping Zhu,Timothy Michael Ramsey,Nicholas Keen,William R. Sellers,Travis Stams,Pascal D. Fortin +52 more
TL;DR: The discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHp2 in an auto-inhibited conformation demonstrates that pharmacological inhibition of SHP1 is a valid therapeutic approach for the treatment of cancers.
Journal ArticleDOI
Mutant KRAS -driven cancers depend on PTPN11 /SHP2 phosphatase
Dietrich A. Ruess,Dietrich A. Ruess,Guus J.J.E. Heynen,Katrin J. Ciecielski,Jiaoyu Ai,Alexandra Berninger,Derya Kabacaoglu,Kivanc Görgülü,Zahra Dantes,S Wörmann,Kalliope N. Diakopoulos,Angeliki Faidra Karpathaki,Marlena Kowalska,Ezgi Kaya-Aksoy,Liang Song,Eveline A.N. Zeeuw van der Laan,María P. López-Alberca,Marc Nazaré,Maximilian Reichert,Dieter Saur,Mert Erkan,Ulrich T. Hopt,Bruno Sainz,Walter Birchmeier,Roland M. Schmid,Marina Lesina,Hana Algül +26 more
TL;DR: The data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers and provide evidence for a critical dependence of mutant KRAS on SHp2 during carcinogenesis.
Journal ArticleDOI
Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes.
K. Martin Kortüm,Elias K. Mai,Nur Hafzan Md Hanafiah,Chang Xi Shi,Yuan Xiao Zhu,Laura Ann Bruins,Santiago Barrio,Patrick Jedlowski,Maximilian Merz,Jing Xu,Jing Xu,Robert A. Stewart,Mindaugas Andrulis,Anna Jauch,Jens Hillengass,Hartmut Goldschmidt,P. Leif Bergsagel,Esteban Braggio,A. Keith Stewart,Marc S. Raab +19 more
TL;DR: A differential genetic landscape in rMM associated with drug response is indicated, with an increased prevalence of mutations in the Ras pathway genes KRAS, NRAS, and/or BRAF as well as TP53, CRBN, and CRBN pathway genes observed.
Journal ArticleDOI
PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs
Anirudh Prahallad,Guus J. J. E. Heynen,Giovanni Germano,Stefan M. Willems,Stefan M. Willems,Bastiaan Evers,Loredana Vecchione,Valentina Gambino,Cor Lieftink,Roderick L. Beijersbergen,Federica Di Nicolantonio,Alberto Bardelli,René Bernards +12 more
TL;DR: An RNA-interference-based genetic screen in BRAF mutant colon cancer cells to search for phosphatases whose knockdown induces sensitivity to BRAF inhibition found PTPN11, which is identified as a drug target to combat both intrinsic and acquired resistance to several targeted cancer drugs.
Journal ArticleDOI
Therapeutic Targeting of Oncogenic Tyrosine Phosphatases
TL;DR: This review will provide topical coverage of target validation and drug discovery efforts made in targeting these oncogenic PTPs as compelling candidates for cancer therapy.
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