SHP099 / Novartis - LARVOL DELTA

SHP2 Inhibition Overcomes Adaptive and Acquired Resistance to FLT3 TKI to Improve Efficacy Against FLT3/ITD AML (ASH 2023) - "The addition of SHP099 to sorafenib decreased the expected ERK reactivation in a dose-dependent manner...The combination of SHP099 with gilteritinib group resulted in a statistically significantly lower leukemia burden compared to either treatment alone and the vehicle control...While daunorubicin or cytarabine alone had little effect on the level of phosphorylated ERK, the addition of SHP099 decreased ERK activation and the combination synergized to exert greater to decrease proliferation and increase apoptosis...The finding that SHP099 synergized with both FLT3 TKI and chemotherapy agents in different FLT3-mutated AML models speaks to the versatile efficacy of SHP2 inhibition in multiple AML models. Taken together, the data suggests that SHP2 inhibition can help overcome both adaptive and acquired resistance in FLT3/ITD AML and is a candidate to try to improve patient outcomes."

Clinical • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AXL • ERBB3 • FLT3

CD169+ Macrophage-Targeted Immunomodulator to Restore Phagocytic Function and Enhance Antigen Presentation for Lymphatic Metastasis Eradication. (PubMed, Adv Sci (Weinh)) - "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."

Journal • Immune Modulation • Immunology • Oncology • CD4

Genetic Deletion or Pharmacologic Inhibition of PTPN11 Impedes the Development and Progression of Myeloproliferative Neoplasms Induced By JAK2V617F and MPLW515L Mutants (ASH 2023) - "The JAK inhibitors, Ruxolitinib and Fedratinib, can reduce splenomegaly and alleviate constitutional symptoms but they are not sufficient to induce remission of MPN. RNA-seq data analysis revealed that genes related to MYC targets, ribosome biogenesis and translation were significantly down-regulated by PTPN11 deletion or SHP099/ruxolitinib combination treatment. Overall, our results suggest that inhibition of PTPN11 alone or in combination with JAK2 inhibition might be useful for treatment of PV and MF."

Essential Thrombocythemia • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis • CALR • CD34 • PTPN11

SHP2 Inhibition Enhances JAK2 Inhibitor Therapy in Preclinical Models of Myeloproliferative Neoplasms (ASH 2023) - "We found that the SHP2 inhibitors RMC-4550 and SHP099 enhanced growth inhibition of MPN model cell lines (e.g., SET2 and UKE1) in combination with ruxolitinib, effectively preventing ruxolitinib persistent growth. Importantly, the combination of SHP2 inhibition using RMC-4550 with JAK2 inhibition using ruxolitinib for 4 weeks in wildtype mice was well tolerated with respect to hematologic parameters and exemplified by no effect on body weight (Panel B). Given SHP2 inhibitors are already undergoing clinical evaluation in patients with solid tumors, our findings suggest that SHP2 is a therapeutic target with potential to be rapidly translated to clinical assessment for MPN patients."

Preclinical • Essential Thrombocythemia • Fibrosis • Hematological Disorders • Hematological Malignancies • Hepatology • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Solid Tumor • Thrombocytosis • CALR • CXCL9 • IL1B • TNFA

Multifunctional macrophage membrane biomimetic nanoparticles for targeted therapy of neovascular age-related macular degeneration. (PubMed, J Control Release) - "Herein, biomimetic nanoparticles (termed SHP/Cur@MNPs) are prepared by co-encapsulating SHP099, an anti-inflammatory and anti-angiogenic agent, and curcumin, an antioxidant, into poly (lactic-co-glycolic acid) (PLGA) coated with macrophage membrane...Furthermore, bioinformatics analysis explored the mechanism of the Hippo signaling pathway in the treatment of SHP/Cur@MNPs against nAMD. Collectively, our study describes a strategy using biomimetic nanoparticles to achieve the synergistic effect by targeting major risk factors associated with nAMD, which might be a novel approach for the safe and effective treatment of nAMD."

Journal • Age-related Macular Degeneration • Inflammation • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

Allosteric SHP2 inhibitors suppress lung cancer cell migration by inhibiting non-canonical activation of EphA2 via the ERK-RSK signaling pathway. (PubMed, Sci Rep) - "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."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • EML4 • KRAS • TNFA

SHP2 inhibitor mitigated renal tubular epithelial cell injury in lupus nephritis via ERK/NF-κB pathway. (PubMed, Clin Exp Rheumatol) - "Our findings suggested that inhibition of SHP2 mitigated renal tubular epithelial cell injury in LN through regulating the ERK/NF-κB signalling pathway. Our study elucidated the mechanism of the beneficial effects of SHP2 inhibitor on LN and provided a promising therapeutic strategy to treat LN."

Journal • Fibrosis • Glomerulonephritis • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Systemic Lupus Erythematosus

SHP2 inhibition by SHP099 attenuates IL-6-driven osteoclastogenesis in growth plate injury. (PubMed, Front Immunol) - "Our findings underscore the pivotal role of SHP2 as a downstream signaling molecule of IL-6 in mediating inflammatory responses during bone repair, suggesting that SHP2 inhibition may present a novel therapeutic approach to prevent pathological bone remodeling and enhance recovery following growth plate injuries. Future investigations should focus on the translational potential of SHP2 inhibitors in pediatric orthopedics."

Journal • Inflammation • Musculoskeletal Diseases • Orthopedics • Pediatrics • CTSK • IL1B • IL6 • PTPN11 • TNFA

GD2-mediated impairment of macrophage phagocytosis drives pulmonary metastasis in osteosarcoma. (PubMed, Theranostics) - "Notably, co-treatment with an anti-GD2 antibody and the SHP2 inhibitor SHP099 resulted in a synergistic reduction of lung metastasis. Our findings uncover a mechanism of osteosarcoma lung metastasis and highlight the GD2-SIGLEC-SHP2 axis as a promising therapeutic target."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

SHP2 is a multifunctional target in anaplastic thyroid carcinoma: Cell intrinsic and immune-dependent anti-tumor effects. (PubMed, Biomed Pharmacother) - "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."

Journal • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • CD8 • PTPN11

Structure-guided expansion strategy unveils potent allosteric SHP2 inhibitors with synergistic efficacy against AML through MCL-1 co-targeting. (PubMed, Eur J Med Chem) - "While allosteric inhibitors like SHP099 have overcome historical challenges of orthosteric agents by stabilizing SHP2's autoinhibited conformation, opportunities remain to enhance potency, selectivity, and clinical utility...Strikingly, B8 demonstrated profound synergy with MCL-1 inhibitor VU661013 in acute myeloid leukemia (AML) models, a novel discovery underscoring the therapeutic potential of dual SHP2/MCL-1 targeting. Our work not only advances the rational design of oral allosteric SHP2 inhibitors but also unveils a critical vulnerability in AML through SHP2-MCL-1 co-targeting, offering a roadmap for combinatorial regimens to improve outcomes in high-risk cancers."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

EGFR/SHP2-targeted antibody-drug conjugate for colorectal cancer theranostics (EACR 2025) - "Cetuximab (Ctx) is an Epidermal Growth Factor Receptor (EGFR)-targeted therapy approved for the treatment of metastatic CRC patients (mCRC)...Towards this goal, we developed an antibody-drug conjugate (ADC) that combines: i) Ctx as a therapeutic anti-EGFR antibody to confer specificity and therapeutic effect; ii) a specific SHP2-inhibitor (SHP099) for cell sensitization; iii) a DOTA chelator for complexation of an imaging radionuclide (67Ga).Material and The synthesis and characterization of an ADC carrying Ctx and SHP099 via maleimide chemistry was performed... We expect to obtain an ADC with improved biological properties for cancer treatment and radiotools to assess EGFR level in tumors. Overall, the proposed dual targeting strategy should promote synergistic therapeutic effects that might overcome resistance to Ctx therapy, enabling a personalized theranostic approach for mCRC."

Colorectal Cancer • Oncology • Solid Tumor • PLCG1

Discovery of SA-8 as a potent SHP2-AUTAC degrader in cancer therapy. (PubMed, Eur J Med Chem) - "Using SHP099 as the ligand of the protein of interest (POI), we designed and synthesized two series of SHP2-AUTACs...It was found that SA-8 can dose-dependently induce apoptosis in HeLa cells. This work not only validates the practical utility of the AUTAC strategy but also offers a promising therapeutic approach for developing next-generation target degraders."

Journal • Oncology • Targeted Protein Degradation

Shp2 regulates the trophoblast cell cycle progression through p53-p21 pathway modulation. (PubMed, Biochem Biophys Res Commun) - "By using a specific Shp2 inhibitor (SHP099) and lentivirus-mediated Shp2 knockdown combined with transcriptome sequencing, we found that Shp2 inactivation significantly inhibited HTR8 proliferation by inducing G0/G1 cell cycle arrest and reduced migratory/invasive capacities...Both pharmacological inhibition and genetic knockdown of Shp2 modulated Erk1/2 and Akt activities, indicating its roles in trophoblast functions through MAPK and PI3K-Akt signaling. This study provides new insights into the molecular mechanisms governing trophoblast biology and potential therapeutic targets for placental disorders."

Journal • Gynecology

SHP2 Allosteric Inhibitor SHP099 Alleviates Inflammation and Restores Salivary Gland Function in Sjögren's Disease-like Animals via Regulation of the IL-17RA Signaling Pathway. (PubMed, Int Immunopharmacol) - "Mechanistically, SHP099 treatment disrupted the IL-17RA/ACT1/TRAF6 signaling axis, phenocopying the effects of SHP2 knockdown and direct IL-17R antagonism, which leads to downregulation of JAK/STAT3 and NF-κB pathways. Collectively, our findings highlight the significant involvement of SHP2 in the pathogenesis of SjD and suggest that targeting SHP2 or its downstream signaling pathways may represent a promising therapeutic approach for SjD treatment."

Journal • Immunology • Inflammation • Sjogren's Syndrome • IL17A • IL17RA • TRAF6

Exploring the allosteric effect of SHP2 Tyr62 phosphorylation on the emergence of acquired resistance to allosteric inhibitor SHP099. (PubMed, J Biomol Struct Dyn) - "Further, Thr108, Phe113, and Glu250 might be the critical residues responsible for the loss of the binding affinity in the pSHP2 - SHP099 complex through a per-residue decomposition analysis and H-bond occupancy time analysis. Overall, this study may provide a mechanistic insight into the mechanism how the allosteric effect of pY62 of SHP2 on SHP099 binding."

Journal • Preclinical

Synergistic blockade of SHP-2 and A2AR signal pathways with targeted nanoparticles restores anti-tumor immunity of CD8+ T cells. (PubMed, J Control Release) - "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."

Journal • Oncology • CD8

Discovery of LC-SF-14, a selective dual inhibitor of SHP2 and FGFR for the treatment of FGFR2-driven gastric cancer. (PubMed, Eur J Med Chem) - "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."

Journal • Gastric Cancer • Oncology • Solid Tumor • FGFR2

SHP099-containing multi-targeting hydrogel promotes rapid skin reconstruction through modulating a variety of cells. (PubMed, Front Bioeng Biotechnol) - "Our results provide new insights into the design of functional hydrogels for tissue regeneration applications. Gel-SHP as a promising tool could provide new clues and new research paradigms for future studies and understanding of the wound healing process and dermal shell formation."

Journal

Targeting PDGFRa-SHP2 signaling enhances radiotherapy in IDH1 mutant glioma (AACR 2025) - "SHP099, a SHP2 inhibitor, reduced GSC tumorigenicity in vitro and in vivo by disrupting SHP2-ERK signaling and promoting differentiation... Combining SHP2 inhibition with RT shows promising therapeutic efficacy for IDH-mut glioma by suppressing the activated SHP2-ERK axis."

Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • IDH1 • PDGFRA

Combined Omipalisib and MAPK Inhibition Suppress PDAC Growth. (PubMed, Cancers (Basel)) - "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."

Journal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • PIK3CA

Profilage chimio-informatique des composés phytochimiques d'Azardirachta indica en tant qu'inhibiteurs oncogènes doubles SHP2/HSP90: identification du nimbocinol, de la nimbidinine et de la margolone. (PubMed, Ann Pharm Fr) - "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."

Journal • Oncology • CDC37 • HSP90AA1

Enhancing KRAS G12D inhibitor sensitivity in pancreatic cancer through SHP2/PI3K pathway. (PubMed, Med Oncol) - "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."

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Combined Omipalisib and MAPK Inhibition Suppress PDAC Growth (Multidisciplinary Digital Publishing Institute) - "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."

Preclinical • Pancreatic Ductal Adenocarcinoma

Targeting PDGFRA-SHP2 Signaling Enhances Radiotherapy in IDH1-Mutant Glioma. (PubMed, Neuro Oncol) - "Combining SHP2 inhibition with RT is a promising therapeutic avenue for IDH-mut glioma by suppressing the activated SHP2-ERK axis."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • IDH1 • PDGFRA