Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer

LaMarche, Matthew J.; Acker, Michael G.; Argintaru, Andreea; Bauer, Daniel; Boisclair, Julie; Chan, Homan; Chen, Christine Hiu-Tung; Chen, Ying-Nan; Chen, Zhouliang; Deng, Zhenghong; Doré, Michaël; Dunstan, David; Fan, Jianmei; Fekkes, Peter; Firestone, Brant; Fodor, Michelle; Garcı́a-Fortanet, Jorge; Fortin, Pascal D.; Fridrich, Cary; Giraldes, John; Glick, Meir; Grunenfelder, Denise; Hao, Huia-Xiang; Hentemann, Martin F.; Ho, Samuel B.; Jouk, Andriana O.; Zhao, Kang; Karki, Rajesh; Kato, Mitsunori; Keen, Nick; Koenig, Robert; LaBonte, Laura R.; Larrow, Jay F.; Liu, Gang; Liu, Shumei; Majumdar, Dyuti; Mathieu, Simon; Meyer, Matthew J.; Mohseni, Morvarid; Ntaganda, Rukundo; Palermo, Mark; Perez, Lawrence; Pu, Minying; Ramsey, Timothy M.; Reilly, John F.; Sarver, Patrick; Sellers, William R.; Sendzik, Martin; Shultz, Michael D.; Slisz, Joanna; Slocum, Kelly L.; Smith, Troy; Spence, Stanley G; Stams, Travis; Straub, Christopher; Tamez, Victoriano; Touré, B. Barry; Towler, Christopher; Wang, Ping; Wang, Hongyun; Williams, S.; Yang, Fan; Yu, Bing; Zhang, Ji-Hu; Zhu, Suzanne

doi:10.1021/acs.jmedchem.0c01170

Cited by 140 publications

(94 citation statements)

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“…These latter sites are enriched on proteins with two nearby phosphotyrosine residues, some of which are directly protected from dephosphorylation by the SH2 domains of SHP2. These data emphasize the two distinct and interrelated biochemical activities of SHP2 -dephosphorylation and phosphosite protectionand identify specific sites relevant to the activity of SHP099 and similar molecules such as TNO155 as therapeutic lead compounds (LaMarche et al, 2020).…”

Section: Introductionmentioning

confidence: 62%

Time-resolved phosphoproteomics reveals scaffolding and catalysis-responsive patterns of SHP2-dependent signaling

Vemulapalli

Chylek

Erickson

et al. 2021

eLife

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SHP2 is a protein tyrosine phosphatase that normally potentiates intracellular signaling by growth factors, antigen receptors, and some cytokines, yet is frequently mutated in human cancer. Here, we examine the role of SHP2 in the responses of breast cancer cells to EGF by monitoring phosphoproteome dynamics when SHP2 is allosterically inhibited by SHP099. The dynamics of phosphotyrosine abundance at more than 400 tyrosine residues reveal six distinct response signatures following SHP099 treatment and washout. Remarkably, in addition to newly identified substrate sites on proteins such as occludin, ARHGAP35, and PLCγ2, another class of sites shows reduced phosphotyrosine abundance upon SHP2 inhibition. Sites of decreased phospho-abundance are enriched on proteins with two nearby phosphotyrosine residues, which can be directly protected from dephosphorylation by the paired SH2 domains of SHP2 itself. These findings highlight the distinct roles of the scaffolding and catalytic activities of SHP2 in effecting a transmembrane signaling response.

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Section: Introductionmentioning

confidence: 62%

Time-resolved phosphoproteomics reveals scaffolding and catalysis-responsive patterns of SHP2-dependent signaling

Vemulapalli

Chylek

Erickson

et al. 2021

eLife

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“…In the absence of in vivo and clinical studies, their utility is limited to in vitro experiments. Nevertheless, the pharmacophoric model, resulting from those studies, may be of great help in identifying novel DGKα inhibitors that might be suitable for clinical use [ 76 , 77 ].…”

Section: Dgkα and Dgkζ Inhibitors As Potential Xlp-1 Therapiesmentioning

confidence: 99%

“…In particular, the SHP-2 inhibitors, SHP099 (100 mg/kg), and FGF401 (30 mg/kg) are used in vivo in FGFR-driven cancer mice models [ 81 ]. Furthermore, TNO155, RMC-4630, JAB-3312 and JAB-3068 are other available validated SHP-2 inhibitors that are in advanced clinical trials for the treatment of various cancers [ 76 , 77 ]. To our knowledge, none of those inhibitors was tested in XLP-1 models until now.…”

Section: Dgkα and Dgkζ Inhibitors As Potential Xlp-1 Therapiesmentioning

confidence: 99%

Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1

Velnati

Centonze

Girivetto

et al. 2021

IJMS

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Diacylglycerol kinases are intracellular enzymes that control the balance between the secondary messengers diacylglycerol and phosphatidic acid. DGKα and DGKζ are the prominent isoforms that restrain the intensity of T cell receptor signalling by metabolizing PLCγ generated diacylglycerol. Thus, their activity must be tightly controlled to grant cellular homeostasis and refine immune responses. DGKα is specifically inhibited by strong T cell activating signals to allow for full diacylglycerol signalling which mediates T cell response. In X-linked lymphoproliferative disease 1, deficiency of the adaptor protein SAP results in altered T cell receptor signalling, due in part to persistent DGKα activity. This activity constrains diacylglycerol levels, attenuating downstream pathways such as PKCθ and Ras/MAPK and decreasing T cell restimulation induced cell death. This is a form of apoptosis triggered by prolonged T cell activation that is indeed defective in CD8+ cells of X-linked lymphoproliferative disease type 1 patients. Accordingly, inhibition or downregulation of DGKα activity restores in vitro a correct diacylglycerol dependent signal transduction, cytokines production and restimulation induced apoptosis. In animal disease models, DGKα inhibitors limit CD8+ expansion and immune-mediated tissue damage, suggesting the possibility of using inhibitors of diacylglycerol kinase as a new therapeutic approach.

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“…At the time of this manuscript preparation, seven type II SHP2 allosteric inhibitors, based on the structure of SHP099, are currently under clinical assessment for adult advanced/metastatic solid tumors, including: TNO155 (NCT03114319, NCT04000529, NCT04330664, NCT04699188, NCT04294160; Novartis) [26,95] 1). Recently, anti-tumor activity of dual intermittent dosing of RMC-4630 (SHP2i) and cobimetinib (MEKi) in patients with KRAS mutant colorectal cancer has been studied, with acceptable tolerability based on preliminary reports.…”

Section: Shp2 Inhibitor-based Therapeutics In Clinical Developmentmentioning

confidence: 99%

SHP2 Inhibition as a Promising Anti-cancer Therapy: Function in Tumor Cell Signaling and Immune Modulation

2021

J Cancer Immunol

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The SHP2 phosphatase consists of one protein tyrosine phosphatase catalytic domain (PTP domain), two tandem Src homology 2 (SH2) domains (N-SH2 and C-SH2), and a C-terminal tail with two tyrosine phosphorylation sites (Tyr542 and Tyr580) [1] (Figure 1A). SHP2 activity is normally auto-inhibited by the binding of the N-SH2 domain with the PTP domain [2]. Upon stimulation of growth factors or cytokines, the N-SH2 domain binds to specific phospho-tyrosine residues and induces a conformational change that leads to exposure of the PTP domain and an increase in the catalytic activity [3] (Figure 1B). Phosphorylated Tyr542 interacts intramolecularly with the N-SH2 domain to relieve steady-state inhibition of the phosphatase, whereas phosphorylated Tyr580 stimulates the phosphatase activity by interaction with the C-SH2 domain [4]. Germline gain of function (GOF) mutations in PTPN11occur in about 50% of patients with Noonan syndrome [5], which is characterized by abnormal facial features, skeletal malformations, congenital heart disease, short stature and an elevated risk of leukemia and other cancers. In contrast, more than 80% of patients with LEOPARD syndrome (lentigines, EKG abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness) harbor heterozygous germline inactivating (phosphatase-defective) mutations in PTPN11, despite the overlapping clinical presentations between this syndrome and those with Noonan syndrome [6,7]. Both conditions are associated with an increased risk for malignancies, including leukemia and neuroblastoma

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Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer

Cited by 140 publications

References 50 publications

Time-resolved phosphoproteomics reveals scaffolding and catalysis-responsive patterns of SHP2-dependent signaling

Time-resolved phosphoproteomics reveals scaffolding and catalysis-responsive patterns of SHP2-dependent signaling

Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1

SHP2 Inhibition as a Promising Anti-cancer Therapy: Function in Tumor Cell Signaling and Immune Modulation

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