SHP099

G-LNP@S-D consists of GM1-functionalized liposomes co-encapsulating the SHP2 inhibitor SHP099 and the STING agonist DMXAA, enabling sequential lymph node- and CD169+ macrophage-specific drug delivery...Importantly, G-LNP@S-D exerts systemic immunomodulatory effects for directly eradicating lymphatic metastases. This study elucidates a sophisticated lymph node immune-modulation strategy and provides a promising therapeutic approach to treat lymphatic metastasis.

We herein demonstrated that the allosteric SHP2 inhibitors, SHP099 and TNO155, suppressed both the TNF-α- and growth factor-induced non-canonical phosphorylation of EphA2 at Ser-897 via the ERK-RSK pathway. In contrast, these inhibitors did not affect the signaling pathways leading to EphA2 induced by TPA in HeLa cells or by TNF-α in A549 cells, indicating the involvement of a complex signaling network in these processes. Collectively, the present results highlight the potential of allosteric SHP2 inhibitors as agents targeting the non-canonical activation of EphA2 in LUAD cells.

Here, we show that SHP2 blockade, by using the SHP099 pharmacologic inhibitor or genetic approaches, significantly affected ATC cell viability, survival, proliferation, motility and stemness assessed by MTS, clonogenic, migration, sphere-forming assays, and Anx-V/PI staining...Consistently, in a syngeneic ATC mouse model, SHP2 inhibition caused an increase of proinflammatory and a decrease of immunosuppressive cytokines/chemokines concomitantly with an increased tumor infiltration of cytotoxic CD8+ T lymphocytes (6,0 ± 8,1 % vs 17,0 ± 8,4 %) and M1 macrophages (14,6 ± 7,6 % vs 29,3 ± 16,2 %) and a reduction in myeloid-derived suppressor cells (MDSCs) (8,5 ± 4,7 % vs 3,9 ± 1,8 %) compared to vehicle-treated group. These findings pose SHP2 as a critical mediator in ATC progression and underscore its potential as a therapeutic target due to its dual role in both directly impeding tumor growth and enhancing immune-mediated anti-tumor responses.

SHP099, an allosteric inhibitor for Src-homology domain-containing protein tyrosine phosphatase-2 (SHP2), and CPI-444, a selected inhibitor for adenosine A2AR receptor, were co-encapsulated in a T cell-targeting nanoparticle (SCNP/αCD8). The enhanced anti-tumor immunity in vivo is also ascribed to improved infiltration of effector CD8+ T cells in tumor tissues. These findings suggest that concurrent blockade of A2AR and SHP2 immune checkpoint signaling pathways with small molecule inhibitors offers a promising alternative strategy to enhance T cell functions for enhanced cancer immunotherapy.

A previous study demonstrated the synergistic effect of the allosteric SHP2 inhibitor SHP099 and the FGFR inhibitor BGJ398, suggesting a potential combined targeted therapeutic option for cancer. LC-SF-14 effectively prevented the phosphorylation of FGFR2 and downstream signaling, resulting in tumor regression in vivo. These results indicate that the bifunctional molecule LC-SF-14, the first PTP- and receptor tyrosine kinase (RTK)-targeted dual inhibitor, is a promising lead for the treatment of cancers bearing SHP2 and FGFR oncogenic drivers.

In vivo oral administration of combined Omipalisib/Trametinib treatment was significantly more effective than Omipalisib/SHP099 in reducing implanted tumor growth, and the Omipalisib/Trametinib treatment more effectively reduced tumor progression and prolonged survival in an aggressive genetically engineered mouse model of PDAC than either Omipalisib or Trametinib alone. Altogether, our data support a rationale for a dual treatment strategy targeting both PI3K and MAPK pathways in pancreatic cancers.

All compounds complied with Lipinski's rule, with margolone showing structural similarities to geldanamycin and SHP099.This study identifies neem-derived compounds as potential dual inhibitors of SHP2 and HSP90, presenting a paradigm shift in cancer therapeutic strategy. These findings provide a foundation for developing novel multi-targeted anticancer therapeutics.

Our study combines MRTX1133 with the SHP2 inhibitor SHP099 or PI3K inhibitor Buparlisib, showing synergistic inhibition of pancreatic cancer cell growth and enhanced apoptosis. These combination therapies could improve clinical outcomes for patients with KRAS G12D  mutation in pancreatic cancer.

Combining SHP2 inhibition with RT is a promising therapeutic avenue for IDH-mut glioma by suppressing the activated SHP2-ERK axis.

We have demonstrated that SHP2 is more expressed in somatotroph tumors, with its pharmacological inhibition resulting in a reduction of both in vitro and in vivo cell proliferation via STAT3 phosphorylation, making this phosphatase a novel clinical target with promising effects on somatotroph tumors.

When we investigated the effect of the combination of alectinib and SHP099 in these novel 3D cultures, we found a comparable cellular response compared with our two-dimensional experiments especially with the drugs in combination. We suggest that 3D cultures be used as preclinical screening platforms to ensure that only the most efficacious drug candidates move on to in vivo testing.

SHP2 plays a pivotal role as a signal transducer in the MAPK/ERK signaling pathway. SHP2 controls the cell cycle via the GSK3β/cyclin D1/Rb pathway in oncogenic KIT-driven GIST. Inhibition of SHP2 synergizes with adjuvant therapy drugs in inhibiting KIT-driven GIST with primary and secondary mutations both in vitro and in vivo.