SCH772984 / Otsuka - LARVOL DELTA

Nicastrin Regulates Cutaneous Squamous Cell Carcinoma Progression Through the MAPK/ERK Signalling. (PubMed, Exp Dermatol) - "To validate the functional relevance of this signalling axis in vivo, we treated NCSTN-knockdown tumour-bearing mice with the ERK inhibitor SCH772984, which effectively suppressed tumour growth. Collectively, these findings demonstrate that loss of NCSTN drives cSCC progression through activation of MAPK/ERK signalling, and identify ERK signalling as a potential therapeutic vulnerability in NCSTN-deficient cSCC."

Journal • Acne Vulgaris • Dermatology • Hidradenitis Suppurativa • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • CLDN3 • NCSTN

Soluble adenylyl cyclase regulates tight junctions of human intestinal epithelial cells via claudin-4. (PubMed, Am J Physiol Gastrointest Liver Physiol) - "While the ERK inhibitor, SCH772984, decreased TEER, ERK did not seem to be involved in the regulation of claudin-4 expression via sAC. Concluding from these data, sAC activity exerts a prominent bidirectional control over the ionic permeability of tight junctions in Caco2Bbe1 monolayers by regulating claudin-4 protein expression via EPAC1. This suggests a pivotal role of sAC in modulation of tight junctions in human intestinal epithelial cells, and proposes a molecular mechanism by which cAMP modulate tight junctions."

Journal • CLDN4

Eleutheroside E alleviates ulcerative colitis by suppressing Th17 immune response via the MAPK signaling pathway and remodeling gut microbiota. (PubMed, Phytomedicine) - "EE, a bioactive molecule derived from a well-known EMH, exerts anti-inflammatory protective effects against acute UC. This protection is associated with the suppression of Th17 immune responses through modulation of the MAPK (MEK/ERK) signaling pathway and a blunted pro-inflammatory microenvironment. These protective effects are also accompanied by gut microbiota remodeling."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • CD4 • IL17A • IL1B • IL23A • IL6 • MAP2K1

Regulatory Mechanism of ERKs Pathway on Orthodontic Force Signal Transduction and Osteogenic Differentiation. (PubMed, J Craniofac Surg) - "The ERKs pathway is a critical mediator of orthodontic force-induced alveolar bone remodeling and OTM, functioning partially through STAT3. These findings establish the ERKs/STAT3 axis as a promising therapeutic target for accelerating orthodontic treatment."

Journal • RUNX2

TREM2 plays a critical role in innate immune defense against acute Toxoplasma gondii infection by promoting macrophage antimicrobial activities. (PubMed, PLoS Pathog) - "TREM2 deficiency has been previously associated with elevated ERK signaling and defective lysosomal activity, and we found that treatment of TREM2 KO macrophages with the ERK inhibitor SCH772984 rescued LAMP1 expression and improved macrophage control of the parasites. Finally, RNA sequencing of myeloid cells isolated from the peritoneal cavity of infected mice at 3 dpi revealed increased transcripts associated with inflammation and decreased transcripts associated with cellular migration in the TREM2 KO compared to WT mice. These findings demonstrate a critical role for TREM2 in the early antimicrobial immune response to T. gondii infection by limiting parasite expansion, dissemination, and pathological inflammation in the infected host."

Journal • Infectious Disease • Inflammation • IL17A • IL6 • LAMP1

Hepatocyte OTUD1 deubiquitinates and activates ERK1/2 to promote acetaminophen-induced liver injury. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "ERK1/2 inhibition by its inhibitor SCH772984 HCl prevented the effect of OTUD1 on APAP-induced liver pathological changes in mice...The new molecular mechanism of APAP-induced hepatocyte injury involves OTUD1-mediated deubiquitination of ERK1/2, leading to enhanced ERK1/2 activity. Therefore, diminishing OTUD1 expression and function may serve as a potential therapeutic target to lessen the adverse response to APAP."

Journal • Hepatology • Inflammation • Liver Failure • Targeted Protein Degradation • OTUD1

WISP-3 promotes tumor-monocyte adhesion through a MEK/ERK-dependent miR-12131/ICAM-4 axis in lung adenocarcinoma. (PubMed, Int J Med Sci) - "Pharmacological inhibition of MEK using PD98059 or U0126, as well as direct inhibition of ERK with SCH772984, markedly attenuated WISP-3-induced ICAM-4 expression and THP-1 adhesion. Collectively, these results demonstrate that WISP-3 promotes ICAM-4-dependent monocyte adhesion through activation of the MEK/ERK pathway and subsequent suppression of hsa-miR-12131. This WISP-3/MEK/ERK/miR-12131/ICAM-4 axis provides new insight into tumor-immune interactions in NSCLC and highlights potential therapeutic targets."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

KCNK4 c.730G>C/p.Ala244Pro Promotes Gingival Fibroblast Proliferation and Fibrosis Through MAPK/ERK1/2 Activation in Gingival Fibromatosis. (PubMed, Int Dent J) - "This study highlights a possible molecular mechanism underlying KCNK4-associated gingival overgrowth and suggests that pathway-based approaches may complement surgical management in future studies. However, further validation in additional patients and preclinical models is required before clinical translation."

Journal • Fibrosis • Immunology • Pediatrics • Solid Tumor • ANXA5 • KCNK4

Erk inhibitors intercept Erk-mediated negative feedback while imposing cell-cycle arrest and activating p38. (PubMed, iScience) - "Provision of either BVD523, GDC0994, SCH772984, ASN007, or Temuterkib, led to strong phosphorylation of Erks, suggesting that all inhibitors intercepted Erks-mediated negative feedback activity...Exposure to BVD523 caused dramatic changes in the phosphoproteome. Thus, the application of Erk's inhibitors should be accompanied by agents that prevent pathway re-activation."

Journal • Oncology

Protein Language Model-Based Fitness Estimates Facilitate Resistance Mutation Identification. (PubMed, J Chem Inf Model) - "A public data set testing ERK2 resistance against the inhibitor SCH772984 and an internal data set testing resistance of an EGFR_exon20 mutant against a Bayer small molecule inhibitor were used...Even though FEP has flagged such mutations as affinity-decreasing and thus potentially resistant, they were not resistant according to the DMS experiment and therefore correctly filtered out. This indicates that protein language model-based protein fitness estimates could be a computationally efficient method to filter mutations without having to model the negative impact of mutations on native function or protein stability, which is error-prone and computationally expensive."

Journal • Oncology

Single-cell and spatial transcriptomic colocalization analysis reveals the roles of histone deacetylation in lung adenocarcinoma progression and microenvironment. (PubMed, Transl Res) - "This study elucidates the pivotal role of HDRGs in LUAD heterogeneity and malignant progression. The FOXA1-HDAC2 axis is identified as a novel regulatory pathway, providing a theoretical and experimental foundation for prognostic stratification and combination targeted therapy in LUAD."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRD2 • FOXA1 • HDAC2

The Interplay of M1 Macrophages and Dental Pulp Stem Cells Promotes Angiogenesis Through IL-8-Dependent VEGF Regulation: An In Vitro Study. (PubMed, Int Endod J) - "M1 macrophages promote angiogenesis via IL-8-induced DPSC VEGF secretion through CXCR1/2-MAPK/ERK-HIF-1α signalling density-dependently, suggesting that therapeutic modulation rather than total suppression of M1 activity could improve outcomes in vital pulp therapy."

Journal • Preclinical • Dental Disorders • Inflammation • CXCL8 • CXCR1 • HIF1A • VEGFA

A Ras family member mediates reciprocal activation of ERK5 and ERK1/2 signaling in response to inhibition of either pathway (EACR 2026) - "Small-molecule inhibitors used included ERK5 inhibitors (JWG-071, XMD8-92), MEK1/2 inhibitor (Trametinib), BRAF inhibitor (Vemurafenib), ERK1/2 inhibitor (SCH-772984) and pan-RAS inhibitor (RMC-6236). X-Ras emerges as the tipping point for the reciprocal compensatory activation of ERK1/2 and ERK5 to overcome single pathway inhibition. Targeting X-Ras potentiates the effects of ERK1/2- and ERK5-directed therapies, highlighting its potential as a combinatorial strategy to overcome MAPK inhibitor resistance in BRAFV600E-mutant melanoma."

IO biomarker • Melanoma • Solid Tumor

ERK1/2 Inhibition Sensitizes AML Cells to the Anthrax Lethanl Toxin-Induced MEK Inhibition (EACR 2026) - "We then tested the impact of the inhibition of ERK1/2, using SCH772984, on the cytotoxicity of LeTx to AML cells.Result and LeTx was cytotoxic to 3 AML cell lines with the remianing 5 showing different levels of resistance to the LF-mediated inhibition of the MAPK pathway... Our findings provide proof of principle for a novel, combined therapy approach for the selective targeting of AML."

Acute Myelogenous Leukemia

PACS2 Alleviates Sepsis-Induced Myopathy by Activating ERK-MAPK Signalling Pathway to Suppress ER-Phagy. (PubMed, J Cachexia Sarcopenia Muscle) - "Our findings demonstrate that SIM is closely associated with disrupted MAM integrity. PACS2 plays a critical role in maintaining MAM structural integrity and regulating FAM134B-mediated ER-phagy through the ERK-MAPK-TFEB signalling axis, thereby providing novel mechanistic insights and potential therapeutic targets for SIM."

Journal • Infectious Disease • Muscular Atrophy • Myositis • Septic Shock • TFEB • VDAC1

MEK/ERK Mediated Diffuse Alveolar Hemorrhage in Murine Lupus (IMMUNOLOGY 2026) - "This study examined the role of the MEK1/2 pathway B6 and BALB/c mice were treated with pristane with or without inhibitors of MEK1/2 (trametinib/GSK1120212 [GSK]), ERK1/2 (SCH772984 [SCH]), JNK, or p38. Pristane treatment promotes lung endothelial injury and DAH in B6 mice by activating the MEK1/2-ERK1/2 pathway and impairing hemostasis. The hereditary factors determining susceptibility to lung injury and bleeding in pristane-induced lupus are relevant to the pathophysiology of life-threatening DAH in systemic lupus erythematosus and may help to optimize therapy."

IO biomarker • Preclinical • Hematological Disorders • Immunology • Inflammatory Arthritis • Lupus • Respiratory Diseases • Systemic Lupus Erythematosus • Vasculitis • EGR1

Abrine targets ERK to suppress EMT and lung metastasis model via MAPKs and Nrf2/Keap-1/HO-1 signaling. (PubMed, Front Immunol) - "Combination with the ERK1/2 inhibitor SCH772984 further enhanced efficacy. Collectively, Abrine exerts potent anti-metastatic effects by directly targeting ERK to inhibit MAPK signaling, reversing EMT and engaging the Nrf2/Keap-1/HO-1 pathway, highlighting Abrine alone or with ERK inhibition as a promising therapeutic strategy against lung metastasis model."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDH1 • CDH2 • IFNG • IL10 • IL17A • KEAP1 • SNAI2 • TGFB1 • TNFA • VIM

Targeting ERK and PI3K signaling in pancreatic ductal adenocarcinoma (AACR 2025) - "Using SCH772984 (an ERK 1/2 inhibitor) and pictilisib (a class I PI3K inhibitor), we evaluated their combined effects on human PDAC cell lines (MIA PaCa-2 and PANC-1) and a patient-derived xenograft (PDX) cell line. Additionally, preclinical testing in animal models will provide critical insights into the therapeutic potential of this combination. This approach represents a promising avenue for improving PDAC treatment outcomes and addressing unmet needs in this aggressive disease."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Extracorporeal Shock Wave Therapy Promotes Peripheral Nerve Regeneration Through ERK1/2-Mediated Autophagy. (PubMed, Ann N Y Acad Sci) - "These effects were amplified by cotreatment with the ERK1/2 agonist senkyunolide I and attenuated by the inhibitor SCH772984. Histological and ultrastructural analyses showed enhanced Schwann cell proliferation, axonal integrity, and myelin reorganization following SWT, alongside improved muscle morphology. Collectively, our findings identify ERK1/2-activated autophagy in Schwann cells as a key mechanism mediating the therapeutic effects of SWT, supporting its translational potential for peripheral nerve repair."

Journal

Dissolvable Microneedle Arrays Loaded with SCH772984 Targeting the MAPK/ERK Pathway to Inhibit Abnormal Vascular Proliferation in Hypertrophic Scars. (PubMed, ACS Biomater Sci Eng) - "This study highlights the critical role of the MAP2K1/ERK pathway in mediating HS angiogenesis. Furthermore, the SCH772984-loaded DMNA platform described here is a promising and minimally invasive transdermal therapeutic approach for the clinical management of HS."

Journal • Dermatology • Fibrosis • MAP2K1

Drug-tolerant pannen cells as precursors of acquired resistance: Opportunities for early intervention against relapse (ENETS 2026) - "mqSCI resolved the longitudinal stress adaptation (0-21 days) to six clinical and ex - perimental anticancer drugs (Temozolomide, Everolimus, Suni - tinib, 5-FU, SCH772984, AUY922) with different mechanisms of action... Our study confirms the presence of DTCs in Pan - NEN according to consensus hallmarks and demonstrates the utility of mqSCI for measuring adaptive reprogramming over time and for developing DTC-specific co-treatment strategies."

Preclinical • Immunology • Metabolic Disorders

Extracellular signal-regulated kinases 1/2 (ERK1/2) is a key regulator of noise-induced hidden hearing loss. (PubMed, Neuroscience) - "Administration of the ERK1/2 inhibitor SCH772984 significantly restored hearing compared with controls. Taken together, our findings demonstrate that noise exposure activates ERK1/2 phosphorylation in the cochlea, leading to hearing loss, and indicate that activation of the ERK1/2 pathway may represent a cellular mechanism underlying NIHHL."

Journal • Otorhinolaryngology

FGF 13 functions as a regulator of the ERK/aerobic glycolysis axis in the inflammatory state during septic lung injury. (PubMed, Nat Commun) - "In addition, SCH772984 (a selective antagonist of ERK signaling) abolishes the aggravation of inflammation in lungs induced by FGF13 overexpression. Our findings demonstrate that FGF13 promotes inflammatory activation upon septic lung injury through the ERK/aerobic glycolysis axis, thereby accelerating the progression of septic lung injury."

Journal • Infectious Disease • Inflammation • Respiratory Diseases • Septic Shock • FGF • HIF1A

PLA2R1-Mediated ERK-Dependent Ferroptosis: A Key Pathogenic Mechanism in Epileptic Neuronal Injury. (PubMed, Exp Cell Res) - "This study identified the PLA2R1-MEK-ERK-ferroptosis signaling axis, suggesting that PLA2R1 contributes to neuronal ferroptosis through ERK pathway activation in epilepsy. PLA2R1's druggability and ERK inhibitors' clinical safety provide foundation for therapeutic translation."

Journal • CNS Disorders • Epilepsy • ACSL4 • GPX4 • PACERR • PTGS2

GOLGB1 deficiency accelerates intervertebral disc degeneration by activating the MAPK pathway. (PubMed, Sci Rep) - "A MAPK signaling pathway inhibitor (SCH772984) strongly reversed this phenomenon and rescued the degeneration of NP cells. These findings suggest that GOLGB1 may be a potential new target for IDD. GOLGB1 is a protective factor against disc degeneration, and knockdown of GOLGB1 accelerates IDD by activating the MAPK pathway."

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