Role of SHP2 in hematopoiesis and leukemogenesis.
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TLDR
SHP2 has emerged as an attractive target for therapeutic targeting in hematological malignancies for its cell autonomous and microenvironmental effects, however a better understanding of the role of SHP2 in different hematopoietic lineages and its crosstalk with signaling pathways activated by other genetic lesions is required before the promise is realized in the clinic.Abstract:
Purpose of reviewSH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11 plays an important role in regulating signaling from cell surface receptor tyrosine kinases during normal development as well as oncogenesis. Herein we review recently discovered roles of SHP2 in normal and aberrread more
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Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?
TL;DR: Novel techniques have been employed to synthesise new inhibitors that specifically attenuate the PTP-dependent signaling inside the cell and amongst them; some are already in clinical development which are discussed in this review.
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Therapeutic potential of targeting SHP2 in human developmental disorders and cancers.
TL;DR: The structure, biological function, deregulation in human diseases, and recent advance in development of SHP2 inhibitors are described to give an insight into the therapeutic potential in future.
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The current state of the art and future trends in RAS-targeted cancer therapies
TL;DR: In this paper , the authors provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies.
Patent
Novel heterocyclic derivatives useful as shp2 inhibitors
TL;DR: In this article, the pyrazine derivatives (I) as SHP2 inhibitors which are shown as formula (I), their synthesis and their use for treating a SHP 2 mediated disorder.
Journal ArticleDOI
SHP2 promotes proliferation of breast cancer cells through regulating Cyclin D1 stability via the PI3K/AKT/GSK3β signaling pathway
Yue Yuan,Yanling Fan,Zicong Gao,Xuan Sun,He Zhang,Zhiyong Wang,Yanfen Cui,Weijie Song,Zhaosong Wang,Fei Zhang,Ruifang Niu +10 more
TL;DR: The mechanism through which tyrosine phosphatase SHP2 regulates breast cancer proliferation is uncovered and may therefore serve as a therapeutic target for breast cancer.
References
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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
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity
Matthew T. Chang,Saurabh Asthana,Sizhi Paul Gao,Byron H. Lee,Jocelyn S. Chapman,Cyriac Kandoth,Jianjiong Gao,Nicholas D. Socci,David B. Solit,Adam B. Olshen,Nikolaus Schultz,Barry S. Taylor +11 more
TL;DR: A statistical algorithm is developed to identify recurrently mutated residues in tumor samples and finds that half of all human tumors possess one or more mutational hotspots with widespread lineage-, position- and mutant allele–specific differences, many of which are likely functional.
Journal ArticleDOI
Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease
Marco Tartaglia,Simone Martinelli,Lorenzo Stella,Gianfranco Bocchinfuso,Elisabetta Flex,Viviana Cordeddu,Giuseppe Zampino,Ineke van der Burgt,Antonio Palleschi,Tamara C. Petrucci,Mariella Sorcini,Claudia Schoch,Robin Foà,Peter D. Emanuel,Bruce D. Gelb +14 more
TL;DR: It is demonstrated that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones and that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHp-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.
Journal ArticleDOI
Normal and Leukemic Stem Cell Niches: Insights and Therapeutic Opportunities
TL;DR: How genetic changes in stromal cells and leukemia-induced BM niche remodeling contribute to blood malignancies are described and how these findings can be applied to non-cell-autonomous therapies targeting the LSC niche are discussed.
Journal ArticleDOI
Dynamics of clonal evolution in myelodysplastic syndromes
Hideki Makishima,Hideki Makishima,Tetsuichi Yoshizato,Kenichi Yoshida,Mikkael A. Sekeres,Tomas Radivoyevitch,Hiromichi Suzuki,Bartlomie J. Przychodzen,Yasunobu Nagata,Manja Meggendorfer,Masashi Sanada,Yusuke Okuno,Cassandra M. Hirsch,Teodora Kuzmanovic,Yusuke Sato,Aiko Sato-Otsubo,Thomas LaFramboise,Naoko Hosono,Yuichi Shiraishi,Kenichi Chiba,Claudia Haferlach,Wolfgang Kern,Hiroko Tanaka,Yusuke Shiozawa,Inés Gómez-Seguí,Holleh D Husseinzadeh,Swapna Thota,Kathryn M Guinta,Brittney Dienes,Tsuyoshi Nakamaki,Shuichi Miyawaki,Yogen Saunthararajah,Shigeru Chiba,Satoru Miyano,Lee Yung Shih,Torsten Haferlach,Seishi Ogawa,Jaroslaw P. Maciejewski +37 more
TL;DR: Significantly enriched in high-risk MDS, TP53, GATA2, KRAS, RUNX1, STAG2, ASXL1, ZRSR2 and TET2 mutations (type 2) had a weaker impact on sAML progression and overall survival than type-1 mutations.
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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