Selective inhibition of leukemia-associated SHP2E69K mutant by the allosteric SHP2 inhibitor SHP099

Sun, X. F.; Ren, Yuan; Gunawan, Steven; Teng, P. K.; Chen, Z; Lawrence, H. Jeffery; Cai, Jianfeng; Lawrence, NJ; Wu, Jingwei

doi:10.1038/s41375-018-0020-5

Cited by 54 publications

(66 citation statements)

References 15 publications

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“…SHP099 has been shown to have antiproliferative activity in human tumour cell lines by inhibition of wild‐type SHP2 that is activated by oncogenic driver RTKs such as EGFR, FLT‐3 and KIT . More recently, SHP099 has been demonstrated to inhibit the growth of a human leukaemia cell line expressing mutant SHP2 (p.Glu69Lys) . Although there is no evidence that canine HS harbours oncogenic driver RTKs, the finding of Sun et al in 2018 suggests the potential utility of SHP099 for growth inhibition of canine HS cells harbouring mutant SHP2 proteins …”

Section: Introductionmentioning

confidence: 99%

“…More recently, SHP099 has been demonstrated to inhibit the growth of a human leukaemia cell line expressing mutant SHP2 (p.Glu69Lys) . Although there is no evidence that canine HS harbours oncogenic driver RTKs, the finding of Sun et al in 2018 suggests the potential utility of SHP099 for growth inhibition of canine HS cells harbouring mutant SHP2 proteins …”

Section: Introductionmentioning

confidence: 99%

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Canine histiocytic sarcoma cell lines with SHP2 p.Glu76Gln or p.Glu76Ala mutations are sensitive to allosteric SHP2 inhibitor SHP099

Tani

Kurita

Miyamoto

et al. 2019

Vet Comparative Oncology

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Some canine cases of histiocytic sarcoma (HS) carry an activating mutation in the src homology two domain-containing phosphatase 2 (SHP2) encoded by PTPN11. SHP099is an allosteric inhibitor of SHP2 that stabilizes SHP2 in a folded, auto-inhibited conformation. Here, we examined the expression and mutation status of SHP2 in five canine HS cell lines and evaluated the growth inhibitory properties of SHP099 against these cell lines. All five of the canine HS cell lines expressed SHP2, with three of the lines each harbouring a distinct mutation in PTPN11/SHP2 (p.Glu76Gln, p.Glu76Ala and p.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Canine histiocytic sarcoma cell lines with SHP2 p.Glu76Gln or p.Glu76Ala mutations are sensitive to allosteric SHP2 inhibitor SHP099

Tani

Kurita

Miyamoto

et al. 2019

Vet Comparative Oncology

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“…The phosphotyrosine binding site is delimited by (i) the A helix, (ii) the BC loop, hereafter referred as pY loop, connecting two strands of the central -sheet, respectively B and C, and (iii) the side chains on the adjacent face of the -sheet. 24 The key residues involved in the interaction with phosphotyrosine are Arg 32 , Thr 42 , and Lys 55 , lining the central -sheet, and residues Ser 34 , Lys 35 and Ser 36 , belonging to the pY loop. 24 Residues Ser 34 , Thr 42 and Ser 36 form hydrogen bonds with the phosphate group, whereas Arg 32 and Lys 55 form salt bridges.…”

Section: Resultsmentioning

confidence: 99%

“…As such, we hope that the allosteric activation mechanism of SHP2 proposed here will support ongoing efforts against genetic disorders involving SHP2. 33,34,35,36…”

Section: Discussionmentioning

confidence: 99%

“…2E-G. Namely, the  state shown in Fig. 2A (transparent) is characterized by (i) a closed pY loop (Lys 35 Cα-Thr 42 Cα distance ~9 Å), (ii) an increased distance between the ends of two -strands, C and D, leading to breaking of three inter-strand hydrogen bonds and spreading of the central -sheet into a Y-shaped structure (Gly 39 C-Asn 58 N distance ~12 Å), and (iii) the closed +5 site with a narrow, less accessible cleft (Tyr 66 Cα-Leu 88 Cα distance ~7 Å; see also Figure 3A, left). The  state shown in Fig A correlation analysis showed that the conformation adopted by the pY loop is strictly coupled to the spread of the central -sheet ( Figure 2B, correlation R = -0.82).…”

Section: The N-sh2 Domain Adopts At Least Two Distinct Conformationsmentioning

confidence: 99%

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An allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase

Anselmi

Hub

2020

Preprint

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SHP2 is a protein tyrosine phosphatase with a key role in multiple signaling pathways, including the RAS-MAPK cascade. Germline mutations in PTPN11, the gene encoding SHP2, occur in 50% of individuals affected by Noonan syndrome, whereas somatic mutations in this gene cause more than 30% of cases of juvenile myelomonocytic leukemia (JMML), and are variably found in other pediatric hematologic malignancies and tumors. Inhibition of the wild-type protein has been recently demonstrated as a novel effective therapeutic strategy for many forms of cancer. Under basal conditions, wild-type SHP2 is inactive because its N-terminal Src homology 2 (N-SH2) domain blocks the active site of the protein tyrosine phosphatase (PTP) domain. Previous work established that binding of a phosphopeptide ligand to the N-SH2 domain causes SHP2 activation by favoring dissociation of the N-SH2 and PTP domains, however the conformational transitions of N-SH2 controlling ligand affinity and PTP dissociation are not well understood. Based on molecular simulations and free-energy calculations, we revealed a 20Å-spanning allosteric network restraining the N-SH2 domain to two distinct states, a SHP2-activating and a stabilizing state. We find that ligand binding is necessary but not sufficient for SHP2 activation, as only ligands selecting for the activating conformation of N-SH2, depending on ligand sequence and binding mode, are predicted to be effective activators. The proposed model of SHP2 activation is further validated by rationalizing modified basal activity and responsiveness to ligand stimulation of N-SH2 variations at residue Tyr 42 . This study provides mechanistic and energetic insight into SHP2 activation and may open novel routes for SHP2 regulation.

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Small‐Molecule Inhibitors of Shp2 Phosphatase as Potential Chemotherapeutic Agents for Glioblastoma: A Minireview

Mitra

Ayyannan

2020

ChemMedChem

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Glioblastoma multiforme (GBM) is a dreadful cancer characterised by poor prognosis, low survival rate and difficult clinical correlations. Several signalling pathways and molecular mediators are known to precipitate GBM, and small‐molecular targets of these mediators have become a favoured thrust area for researchers to develop potent anti‐GBM drugs. Shp2, an important phosphatase of the nonreceptor type protein tyrosine phosphatase (PTPN) subfamily is responsible for master regulation of several such signalling pathways in normal and glioma cells. Thus, inhibition of Shp2 is a logical strategy for the design and development of anti‐neoplastic drugs against GBM. Though tapping the full potential of Shp2 binding sites has been challenging, nevertheless, many synthetic and natural scaffolds have been documented as possessing potent and selective anti‐Shp2 activities in biochemical and cellular assays, through either active‐site or allosteric binding. Most of these scaffolds share a few common pharmacophoric features, a thorough study of which is useful in paving the way for the design and development of improved Shp2 inhibitors. This minireview summarizes the current scenario of potent small‐molecule Shp2 inhibitors and emphasizes the anti‐GBM potential of some important scaffolds that have shown promising GBM‐specific activity in in vitro and in vivo models, thus proving their efficacy in GBM therapy. This review could guide researchers to design new and improved anti‐Shp2 pharmacophores and develop them as anti‐GBM agents by employing GBM‐centric drug‐discovery protocols.

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Selective inhibition of leukemia-associated SHP2E69K mutant by the allosteric SHP2 inhibitor SHP099

Cited by 54 publications

References 15 publications

Canine histiocytic sarcoma cell lines with SHP2 p.Glu76Gln or p.Glu76Ala mutations are sensitive to allosteric SHP2 inhibitor SHP099

Canine histiocytic sarcoma cell lines with SHP2 p.Glu76Gln or p.Glu76Ala mutations are sensitive to allosteric SHP2 inhibitor SHP099

An allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase

Small‐Molecule Inhibitors of Shp2 Phosphatase as Potential Chemotherapeutic Agents for Glioblastoma: A Minireview

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