SHP099 / Novartis - LARVOL DELTA

Discovery of highly potent and efficacious Bromodomain and Extra-terminal (BET) degraders with activity against acute myeloid leukemia and triple-negative breast cancer. (PubMed, Eur J Med Chem) - "Through structural optimization, 36 (F364) was identified as a potent BRD4 degrader, exhibiting a Dmax of 93.96% and a DC50 of 0.676 nM in the HiBiT assay using HEK293-BRD4-HiBiT-KI cells, slightly superior to the positive control ARV-825. This compound showed strong antiproliferative activity in MV4-11 cells (IC50 = 4.99 nM) and displayed marked efficacy against SHP099-resistant MV4-11 cells (IC50 = 1.62 nM), indicating its potential to overcome resistance to SHP2 inhibitors...In xenograft mouse models using MV4-11 and MDA-MB-231 cells, F364 demonstrated significant antitumor efficacy without observable toxicity. In summary, F364 has been identified as a novel and potent BRD4 degrader, showing promising therapeutic potential for the treatment of acute myeloid leukemia and triple-negative breast cancer."

Journal • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Immunology • Leukemia • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRD4 • CRBN

Deciphering SHP-2 conformational switching via elastic network models and transfer entropy analysis. (PubMed, J Mol Model) - "Here, we employed an equal-weighted multi-parameter Gaussian network model (ewmGNM) to investigate the two lowest-frequency modes governing the functional dynamics of SHP-2 in three key systems: the wild-type closed (autoinhibited) conformation, the oncogenic E76K mutant in its open (active) conformation, and its complex with the allosteric inhibitor SHP099...The ewmGNM and the conventional GNM were implemented using custom scripts written in MATLAB R2024b. Protein dynamics data were mapped using custom Python scripts in PyMOL."

Journal • Oncology • PTPN11

Bacterial Killing by Human CF Airway Neutrophils Is Modulated by the PD-1/SHP2 Axis and Ameliorated by Immune Checkpoint Inhibitor Therapy (NACFC 2026) - "Rescue of their bactericidal activity against P. aeruginosa was attempted by immune checkpoint inhibitor (ICI) treatment combining with an anti–PD-1 antibody with a SHP2 inhibitor SHP099... The PD-1 / SHP2 axis is involved in the modulation of bacterial clearance or tolerance by airway-recruited neutrophils. PDL-1 on neutrophils is the likely ligand for activation of this immune checkpoint, as we previously demonstrated for PD-1 ligation on macrophages in children with CF [3]. Together, our published data on macrophages and data presented here on neutrophils support further exploration of ICI, repurposed from other domains of medicine, as a mutation-agnostic approach to reenergize bacterial killing by CF airway myeloid cells, irrespective of HEMT status."

Checkpoint inhibition • IO biomarker • Immunology • Infectious Disease • Oncology

Inhibition of SHP2 enhances the effects of selective receptor tyrosine kinase inhibitors in untreated preclinical models of RET-mutated thyroid cancer. (PubMed, Invest New Drugs) - "Although selective RET inhibitors such as selpercatinib (LOXO-292) and pralsetinib (BLU-667) induce significant clinical responses, adaptive resistance frequently arises through reactivation of MAPK signaling...RET-mutated thyroid cancer cell lines (TPC-1 and TT) were treated with selective RET inhibitors alone or in combination with the SHP2 inhibitor SHP099...These findings support SHP2 as an important mediator of adaptive ERK reactivation following RET inhibition. Dual blockade of RET and SHP2 produces more durable MAPK pathway suppression and enhances antitumor efficacy in the models tested, providing a rationale for further evaluation of this combination in RET-altered thyroid cancer."

Journal • Preclinical • Oncology • Solid Tumor • Thyroid Gland Carcinoma • EGFR • FGFR2 • PDGFRB • RET

Discovery of DCAF16-based PROTACs as SHP2 degraders. (PubMed, Bioorg Chem) - "Notably, under the tested experimental conditions, SK8 produced greater inhibition of cell proliferation, migration, and invasion, together with increased apoptosis, compared with SHP099. Preliminary mechanistic studies revealed that this enhanced potency stemmed from a more profound inhibition of RAS/MAPK and PI3K/AKT/mTOR signaling, coupled with the reversal of IFN-γ/JAK/STAT1 suppression. Overall, our findings support the potential of SHP2-targeted protein degradation as an alternative strategy to enzymatic inhibition and provide a promising starting point for the further development of SHP2 degraders."

Journal • Oncology • Targeted Protein Degradation • IFNG • STAT1

SHP2 Inhibition Enhances Responses to Anti-PD1 Immunotherapy in Head and Neck Cancer Models (AHNS 2026) - "These results suggest further study into the use of SHP099 as a drug that may enhance responses to PD-1 immunotherapies. Furthermore, our in vitro results suggest that increases in APM afforded by this drug may be limited, and further studies into the mechanisms of SHP099, including direct activation of T cells, should be explored."

IO biomarker • Preclinical • Colon Cancer • Head and Neck Cancer • Lung Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • IFNG • STAT1

EBV-informed multi-omics target prioritization and structure-based drug repurposing reveal potential therapeutic strategies for multiple sclerosis. (PubMed, Funct Integr Genomics) - "Structure-based drug repurposing identified Gusperimus as the top-ranked ligand, exhibiting a favorable docking score (- 9.287 kcal/mol) and a broader interaction profile within the SHP2 allosteric pocket relative to the reference inhibitor SHP099 (- 7.915 kcal/mol). Molecular dynamics simulations supported stable occupancy of the SHP2 allosteric pocket by Gusperimus over a 100 ns trajectory. Collectively, these findings highlight SHP2 as a potential therapeutic target and identify Gusperimus as a candidate for further investigation in MS-associated immune dysregulation."

Journal • CNS Disorders • Epstein-Barr Virus Infections • Infectious Disease • Inflammation • Multiple Sclerosis • CD14 • CD8 • CD86 • IL6 • PTPN11

Gain-of-function mutations in SHP2 enhance megakaryopoiesis through the Ras/MAPK pathway downstream of the c-KIT and MPL receptors (ISTH 2026) - "The allosteric SHP2 inhibitor SHP099 was also used...This results in enhanced MAPK activation, progenitor expansion, and proliferation. DOI*10.1016/j.rpth.2026.105123"

Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Immunology • Juvenile Myelomonocytic Leukemia • Leukemia • Myeloproliferative Neoplasm • CD33 • CD34 • ITGA2B • KIT • PI3K • PTPN11 • SPN

CRISPR/Cas9-mediated deletion of Shp1 and Shp2 reveals a critical role for Shp2 in human megakaryopoiesis (ISTH 2026) - "Shp2 activity was inhibited using the allosteric inhibitors Shp099 and RMC-4550. Given the constitutive activation of JAK2/Mpl signaling in myeloproliferative neoplasms, Shp2 represents a promising therapeutic target to modulate pathological thrombopoiesis. DOI*10.1016/j.rpth.2026.105132"

Myeloproliferative Neoplasm • CD34 • PTPN11 • RHOA

Zinc finger protein-associated gene signature serves as a potential predictor for prognosis and therapeutic response in lung adenocarcinoma. (PubMed, Amino Acids) - "Possible therapeutic compounds for LUAD patients included SHP-099, Dimethylfasudil, EMD-534085, and PF-2771. The expression of CTCFL enhanced the malignant cellular behavior in LUAD. ZNFs-related gene signature provides predictive insights into LUAD patient survival, immune cell infiltration, and immune checkpoint blockade therapy, serving as a valuable tool to guide clinical decision-making."

Gene Signature • IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CBFA2T3 • IGF2BP1 • KLF10 • TRIM29 • ZIC2

Discovery of Novel Dual Small-Molecule Inhibitors Targeting SHP2 and NAMPT for Overcoming Resistance to Allosteric SHP2 Inhibition. (PubMed, J Med Chem) - "A4 effectively inhibited proliferation in SHP099-insensitive tumor cell lines and reversed programmed cell death ligand 1 (PD-L1)-mediated immunosuppression. Furthermore, A4 displayed significant in vivo antitumor efficacy in an MDA-MB-231 mouse model and strongly promoted in vivo antitumor immunity in a 4T1 mouse model. Our results identified A4 as a promising dual SHP2 and NAMPT inhibitor, providing a novel therapeutic strategy for overcoming resistance to allosteric SHP2 inhibition."

Journal • Oncology • NAMPT • PD-L1

LAPF enhances lysosomal acidification to promote TLR9 and cGAS-STING-mediated antiviral immunity and attenuate HSV-1-induced neuroinflammatory pain. (PubMed, J Neuroinflammation) - "This effect was abolished by lysosomal acidification inhibitor chloroquine (CQ), supporting that LAPF promotes lysosomal acidification-dependent antiviral immunity via TLR9 and cGAS-STING pathways. Pharmacological enhancement of LAPF activity using the dephosphorylation inhibitor SHP099 alleviated neuroinflammation and mechanical allodynia in HSV-1-induced neuroinflammatory pain model mice, suggesting potential therapeutic implications. In conclusion, our findings demonstrate that LAPF enhances lysosomal acidification to promote dual antiviral innate immune responses via TLR9 and cGAS-STING pathways in HSV-1 infection, thereby attenuating HSV-1-induced neuroinflammatory pain. These results provide mechanistic insights and potential therapeutic targets for virus-associated neuroinflammatory pain."

Journal • Herpes Simplex • Infectious Disease • Inflammation • Neuralgia • Pain • CGAS • STING • TLR9

Vertical MAPK pathway targeting is required for tumor regression in novel human and mouse models of NF1-inactivated melanoma (AACR 2026) - "While the MEK inhibitor selumetinib has been FDA approved for pediatric patients with Neurofibromatosis type 1 with benign plexiform neurofibromas arising from germline NF1 mutation, MEK inhibitors and other therapies targeting the MAPK pathway have had limited clinical benefit in patients with tumors driven by NF1-inactivation...As anticipated, loss of Nf1 conditioned the response to treatment with a BRAF monomer inhibitor (vemurafenib). While Nf1-inactivated cells were more sensitive to MEK inhibition (trametinib), or combined BRAF/MEK inhibition, as seen by suppression of ERK phosphorylation (pERK), cyclin D1 and DUSP6 expression, and cell proliferation, levels of pERK quickly rebounded. BRAF V600E/NF1/TP53-mutant cells were also transiently sensitive to combined inhibition of BRAF and the positive RAS adaptor SHP2 (using SHP099); with the rebound of pERK mitigated only by MEK, not upstream BRAF/SHP2, inhibition. In mice with established BrafCA/Nf1/Trp53-null tumors..."

Preclinical • Brain Cancer • Glioma • Melanoma • Oncology • Solid Tumor • CCND1 • DUSP6 • NF1

FGFR3 altered bladder cancer exhibits a lineage-dependent vulnerability (AACR 2024) - "Moreover, the synergy in FGFR3-mutant cells was superior to that of SHP2 inhibitor SHP099 or the ERK inhibitor BVD-523...By contrast, Sel120+Erdafitinib induced complete responses in 8/10 mice compared to 6/10 mice for SHP099+Erdafitinib...Our results suggest an immediate and promising benefit in combining either CDK8/19 or SHP2 inhibitors with Erdafitinib in treating patients with FGFR3 alteration driven bladder cancers. Furthermore, we identified a strategy in targeting lineage modulators as sensitizers to existing therapies."

Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • FGFR3 • GATA3 • PPARG

Investigating a non-canonical role for SHP2 in pancreatic ductal adenocarcinoma metabolism and response to dietary modifications (AACR 2024) - "We utilized available RNAseq data (NCBI GEO: PRJNA558508) of PDAC MiaPaCa2 cells treated with the MEK inhibitor, Trametinib, or SHP099 to compare the direct effects of inhibition on transcriptional outcomes. Western diets have been shown to promote tumor progression in GEM models of PDAC, so we used KRASG12D/+, SHP2fl/fl or wt./wt, Ptf1aCre/+ (SKC and KC) mice to demonstrate that while diet-induced obesity affects KC tumor burden, the lack of SHP2 in SKCs prevents the diet associated discrepancy in tumor progression. Collectively, these data led us to conclude that while SHP2 has been studied as a contributor to KRAS signaling in PDAC, the outcomes of its role specifically on mitochondrial metabolism have yet to be appreciated or thoroughly investigated, opening the path for a new approach to its contribution to tumor progression."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • IL1B • KRAS

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

An allosteric SHP2 inhibitor suppresses breast cancer-induced osteoclastogenesis and bone lysis. (PubMed, Biochem Pharmacol) - "In a murine model of MDA-MB-231-induced osteolytic lesions, oral administration of 10 mg/kg SHP099 reduces osteoclasts and prevents the trabecular bone loss. Our study identifies SHP2 as a druggable target for inhibiting breast cancer-induced osteoclast differentiation, positioning the specific inhibitors of SHP2 as potential drugs developed to treat tumour-induced osteolysis in the future."

Journal • Breast Cancer • Oncology • Solid Tumor • FOS • NFATC1

Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations (Nature) - "We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency. Anabolic pathways, autophagy and glycolysis were also profoundly altered. However, most strikingly, mitochondrial remodeling was evident, persisting into a therapy-resistant state. The resulting vulnerability to the induction of ferroptotic cell death via the combination of vertical SHP2/MEK1/2 with glutathione peroxidase (GPX4) inhibition was largely independent of the PDAC molecular subtype and was confirmed with direct targeting of RAS."

Preclinical • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Structural insights into the binding modes of SHP2 allosteric inhibitors. (PubMed, In Silico Pharmacol) - "Efforts to develop SHP2 allosteric inhibitors, such as SHP099, have laid the foundation for SHP2-targeted therapeutics...These findings provide insights into the molecular interactions of SHP2 allosteric inhibitors under physiologically relevant conditions, which will guide the optimization of the structural design of pyrazine-class SHP2 allosteric inhibitors. The online version contains supplementary material available at 10.1007/s40203-025-00551-x."

Journal • Cardiovascular • Oncology

Inhibiting SHP2 improves ventricular remodeling by restoring AMPK phosphorylation and mitochondrial homeostasis. (PubMed, Cell Commun Signal) - "This study demonstrates that SHP2 acts as a key phosphatase directly dephosphorylates AMPK, thereby triggering mitochondrial dysfunction and exacerbating ventricular remodeling. Our findings provide novel mechanistic insights into heart failure progression and highlight SHP2 as a potential therapeutic target for heart failure treatment."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Metabolic Disorders • AMPK

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