ralimetinib (LY 2228820) / Eli Lilly - LARVOL DELTA

Systems-level exploration of Withania somnifera-derived phytochemicals against breast cancer: A network pharmacology and molecular modeling approach. (PubMed, Comput Biol Med) - "Therefore, Viscosalactone B and Withasomniferol C are promising natural candidates for further validation as potential MAPK14 inhibitors. In comparison with synthetic drugs like ralimetinib, these plant-derived compounds may offer complementary therapeutic potential with fewer adverse or off-target effects and favorable pharmacokinetic and pharmacophoric profiles."

Journal • Breast Cancer • Infectious Disease • Oncology • Solid Tumor • AKT1 • EGFR • MAPK14 • PIK3R1 • RELA • STAT3

Targeting Pro-Metastatic Stress Kinase Networks in Triple-Negative Breast Cancer Using Patient-Derived Models (SABCS 2025) - " We show that combinations of 3 kinase inhibitors used in early phase clinical trials (Ralimetinib (p38), JNK-in-8 (JNK) or FDA approved (Trametinib (MEK & ERK1/2)) inhibit stress kinase networks, pro-motility gene expression and TNBC cell invasion. Inhibition of these stress kinase networks should enable effective reprogramming of metastatic or high-risk cancers to more benign states and make tumors more susceptible to approved anti-proliferative therapies such as chemotherapy or immunotherapy while limiting toxicities from kinase inhibitors using a low-dose, multi-drug combination approach."

Clinical • IO biomarker • Metastases • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BACH1 • BRIP1 • PEBP1

Targeting neuron-glioma chloride cross-talk in glioblastoma (SNO 2025) - "Pretreatment of GBM cells with the MK2 inhibitor ralimetinib restored chloride balance and reduced neuronal hyperexcitability. Collectively, these findings reveal a paracrine mechanism of chloride transfer between glioma cells and neurons, highlighting chloride signaling as a novel therapeutic target to inhibit neuronal hyperexcitability and tumor proliferation in glioblastoma multiforme (GBM)."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • MAPKAPK2 • SLC12A2

Targeting neuron-glioma chloride cross-talk in glioblastoma (WFNOS 2025) - "Pretreatment of GBM cells with the MK2 inhibitor ralimetinib restored chloride balance and reduced neuronal hyperexcitability. Collectively, these findings reveal a paracrine mechanism of chloride transfer between glioma cells and neurons, highlighting chloride signaling as a novel therapeutic target to inhibit neuronal hyperexcitability and tumor proliferation in glioblastoma multiforme (GBM)."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • MAPKAPK2 • SLC12A2

A crucial role of DUSP8 in glioblastoma by endothelial transdifferentiation inhibition of Glioblastoma Stem-like Cells (ECP 2025) - "These findings suggest that regulating the miR-1825/DUSP8 pathway could be a therapeutic strategy to inhibit tumor vascularization in GBM."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • MIR182

A crucial role of DUSP8 in glioblastoma by endothelial transdifferentiation inhibition of Glioblastoma Stem-like Cells (ECP 2025) - "These findings suggest that regulating the miR-1825/DUSP8 pathway could be a therapeutic strategy to inhibit tumor vascularization in GBM."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • MIR182

Advances in targeting p38 MAPK for cancer therapy: insights from molecular pharmacology and medicinal chemistry. (PubMed, Mol Divers) - "Two major classes of p38 inhibitors are highlighted: ATP-competitive inhibitors that block the kinase by targeting the ATP-binding pocket (e.g., SB203580, Ralimetinib), and allosteric inhibitors that interact with regulatory regions outside the active site, inducing conformational changes to suppress kinase activity (e.g., BIRB796)...This review also emphasizes the therapeutic challenges, subtype selectivity, and opportunities for isoform-specific drug design. Ultimately, a comprehensive understanding of these mechanisms can support the rational development of p38 MAPK inhibitors with improved efficacy and selectivity in oncology."

Journal • Review • Oncology

Targeting pro-metastatic stress networks in triple-negative breast cancer using patient-derived models (AACR 2025) - "We show that combinations of kinase inhibitors used in early phase clinical trials (Ralimetinib (p38), JNK-in-8 (JNK) or FDA approved (Trametinib (MEK & ERK1/2)) can inhibit stress kinase networks, pro-motility gene expression and TNBC cell migration. We utilized mass spectrometry-based techniques with a kinase inhibitor system (MIB-MS) and proteomics to characterize the activation state of kinase signaling networks in organoids and are investigating the effect of metastatic inhibitors on these pathways. Inhibition of these stress kinase networks should enable effective reprogramming of metastatic or high-risk cancers to more benign states and make tumors more susceptible to approved anti-proliferative therapies such as chemotherapy or immunotherapy while limiting toxicities from kinase inhibitors using a low-dose, multi-drug combination approach."

Clinical • IO biomarker • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BACH1 • BRIP1 • HER-2 • PEBP1

Role of the ETV5/p38 Signaling Axis in BRAF-Mutated Anaplastic Thyroid Cancers (ATA 2024) - "Among three different p38 inhibitors tested in vitro, ralimetinib was the most effective (IC50 @ 15 mM). We have identi fied a connection between the MAPK and the p38 pathways, which relies on ETV5 expression. Activation of the MAPK/ETV5 axis by the BRAF V600E mutation upregulated the p38 pathway, which may contribute to additional cell survival/proliferation and resistance. Combining inhibitors targeting BRAF V600E (such as dabrafenib) and p38 activity showed synergistic effects, yet enhancing the speci ficity of the latter will be crucial to pave the way for a novel strategy in treating BRAF-mutated ATC and PDTC thyroid cancers."

Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • ATF2 • BRAF • ETV5 • MAP2K3

Chemical genetics analysis suggests the involvement of Aurora kinase and MAPKs in aluminum-induced malate secretion in Arabidopsis. (PubMed, J Plant Res) - "An increase in root elongation was also observed in Arabidopsis after applying compounds LY2228820 and MLN8237. Thus, both LY2228820 and MLN8237 may play important roles in alleviating the inhibitory effects of aluminum on roots."

Journal • AURKA

Knocking out deadly brain cancer with a dual therapy (Medical Xpress) - "The researchers implanted ME cells from patients into mice. They found that mice treated with a combination of p38MAPK inhibitor ralimetinib, MEK inhibitor binimetinib, and TMZ had the best survival of 72.5 days compared to mice treated with TMZ alone (63 days)....Ralimetinib and binimetinib inhibited p38MAPK and MEK/ERK, respectively, restoring the effectiveness of TMZ against ME. Inhibiting p38MAPK also decreased the expression of various drug transporter proteins and enhanced the retention of TMZ in cells."

Preclinical • Glioblastoma

A synergy between MDM2 and AURKB pathways in driving cell cycle and cell survival in lung cancer cells (AACR 2024) - "Therefore, the main objective of this study was to understand the molecular mechanisms linking MDM2 and ARKB using RG7388, CM272, BMS-582949 (p38 inhibitor), and Ralimetinib (p38 inhibitor) in A549 and H460 lung cancer cells. (This project was supported by the PFRDG Grant of Nova Southeastern University and by the Generous support from the Royal Dames of Cancer Research Ft. Lauderdale, FL)"

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKB • CDK4 • CDKN1A • DNMT1 • DNMT3A • FOXM1 • FOXO3 • GNRP • MDM2 • RASGRF1

Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide. (PubMed, Neuro Oncol) - "Temozolomide resistance in mesenchymal glioblastoma is associated with p38MAPK activation. Adaptive chemoresistance in p38MAPK-resistant cells is mediated by MEK/ERK signaling. Adjuvant therapy with dual p38MAPK and MEK inhibition prolongs temozolomide sensitivity, which can be developed into a precision therapy for the mesenchymal subtype."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Melanoma • Oncology • Solid Tumor

p38 Mitogen-Activated Protein Kinase Inhibition of Mesenchymal Transdifferentiated Tumor Cells in Head and Neck Squamous Cell Carcinoma. (PubMed, Biomedicines) - "We investigated the growth inhibitory, cisplatin-sensitizing, and pro-apoptotic effects of p38 MAPK inhibition in cisplatin-resistant (SCC-25) and -sensitive (UPCI-SCC090) HNSCC cell lines, using two specific p38 MAPK inhibitors, SB202190 and ralimetinib. In accordance, p-p38 inhibition led to sensitization of pEMT cells to cisplatin-induced cell death; moreover, p-p38 inhibitor treatment cycles significantly decreased the viability of cisplatin-surviving cells. In conclusion, clinically relevant p38 inhibitors might be effective for RCT-resistant pEMT cells in HNSCC patients."

Journal • Tumor cell • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • SNAI2 • TGFB1

Drug repurposing for the treatment of COVID-19: Targeting nafamostat to the lungs by a liposomal delivery system. (PubMed, J Control Release) - "Ralimetinib and nafamostat, clinically used drugs, have emerged as attractive candidates. In summary, we were able to demonstrate a proof-of-concept of drug repurposing by liposomal formulations with anti-SARS-CoV-2 activity. The biodistribution and bioactivity studies with LipNaf suggest an IN or inhalation route of administration for optimal therapeutic efficacy."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • APOB

Uncoupling p38α nuclear and cytoplasmic functions and identification of two p38α phosphorylation sites on β-catenin: implications for the Wnt signaling pathway in CRC models. (PubMed, Cell Biosci) - "p38α seems to play a dual role as a member of the β-catenin destruction complex and as a β-catenin chromatin-associated kinase in CRC. This finding may help elucidate mechanisms contributing to human colon tumor pathogenesis and devise new strategies for personalized CRC treatment."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CTNNB1 • WNT3

Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor. (PubMed, Cell Chem Biol) - "We conclude that, though ralimetinib is >30-fold less potent against EGFR compared to p38α, its ability to inhibit EGFR drives its primary anticancer effects. Our results call into question the value of p38α as an anticancer target, and we describe a multi-modal approach that can be used to uncover a drug's mechanism-of-action."

Journal • Oncology

Integrative multiomics analysis of poor risk AML rationalizes differential drug responses in cases with mature and primitive molecular landscapes (EACR 2023) - "Classification of AML cases into primitive (n=12) and mature (n=10) revealed that primitive cells were more sensitive to 22 compounds including azacitidine and navitoclax. In contrast, mature cells were preferentially sensitive to 17 compounds including the MLC1 inhibitor A-1210477, the TLR8 agonist motolimod, the ROS inducer auranofin and 4 IAPs inhibitors...Mature cells increased the phosphorylation of stress response proteins like ASK1, P38A, JNK1 at and ATF7 at regulatory sites, but were more resistant to the P38 and JNK inhibitors ralimetinib and tanzisertib, respectively.ConclusionThe higher activity of the stress response pathway in mature cells could be the reason for their higher sensitivity to compounds that either induce (Auranofin) or modulate (IAPs inhibitors) the stress response. Overall, our integrative analysis is a rich source of molecular information to rationalize specific drug sensitivities of poor risk AML cases with mature and primitive phenotypes...."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Aplastic Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • MAPK8 • TLR8

Dickkopf-1 (DKK1) mediates proteostatic stress-induced cytokine response in prostate and breast cancer (EACR 2023) - "Material and MethodsHuman prostate cancer cells (PC3, DU145) and breast cancer cells (MDA-MB-231) were treated with the chemical endoplasmic reticulum stress inducers thapsigargin (Tg) or tunicamycin (Tm). Ralimetinib was used for p38-signaling inhibition...These results indicate that DKK1 deficiency sensitizes PC3 cells to proteostatic stress.ConclusionOur data indicate DKK1 as a potential target in sensitizing tumor cells to ER stress inducers. Additional experiments and in vivo models are needed to further dissect the role of DKK1 in tumor cell ER stress."

Breast Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ATF6 • DKK1 • ERN1 • IL1B • IL6

Effect of the loss of NF1 in breast cancer on pathway activation. (ASCO 2018) - "...The MEK inhibitors trametinib and PD0325901 (IC50= 0.25 nM and 0.16 nM, respectively) inhibited growth of NF1-null, but not parent cells. We explored inhibitors of other proteins in the MAPK signaling pathway, including the Raf inhibitors sorafenib and vemurafenib and the dual MAP3K1/MAP2K4 inhibitor LY2228820...Vincristine and zoledronic acid can indirectly affect Rho GTPase function...Similar sensitivity was not observed to docetaxel or ixabepilone... Our results suggest that loss of NF1 results in a transformed phenotype. The NCI MATCH program currently lists the MEK inhibitor trametinib as the drug of choice for any tumor harboring mutant NF1. Our results provide the first evidence that this drug could be efficacious in breast cancers."

Breast Cancer • Oncology • Solid Tumor

Anticancer Mechanism of Flavonoids on High-Grade Adult-Type Diffuse Gliomas. (PubMed, Nutrients) - "This review discusses the anticancer mechanism of flavonoids (quercetin, rutin, chrysin, apigenin, naringenin, silibinin, EGCG, genistein, biochanin A and C3G) through targeting molecules associated with high-grade adult-type diffuse glioma cell proliferation, apoptosis, oxidative stress, cell cycle arrest, migration, invasion, autophagy and DNA repair. Moreover, the clinical relevance of flavonoid molecular targets in high-grade adult-type diffuse gliomas is discussed with comparison to small molecules inhibitors: ralimetinib, AMG232, marimastat, hydroxychloroquine and chloroquine. Despite the positive pre-clinical results, further investigations in clinical studies are warranted to substantiate the efficacy and safety of the use of flavonoids on high-grade adult-type diffuse glioma patients."

Journal • Review • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • BAX • BCL2 • BECN1 • CASP3 • CASP8 • MMP2 • MMP9

c-MYC Protein Stability Is Sustained by MAPKs in Colorectal Cancer. (PubMed, Cancers (Basel)) - "Extensive molecular analyses in the cellular and in vivo models revealed that the p38α kinase inhibitors, SB202190 and ralimetinib, affect c-MYC protein levels. Ralimetinib also exhibited a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Overall, our findings identify p38α as a promising therapeutic target, acting directly on c-MYC, with potential implications for countering c-MYC-mediated CRC proliferation, metastatic dissemination, and chemoresistance."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CTNNB1 • MYC

Dual inhibition of MDM2 and p38 MAPK signaling is a potential therapeutic strategy in esophageal squamous cell carcinoma (AACR 2022) - "In this study, we aimed to investigate the effect of combining a p38 MAPK inhibitor and an MDM2 antagonist as a potential therapeutic strategy in ESCC. To determine the synergistic anti-tumor activity of the MDM2 antagonist siremadlin (HDM-201) and the p38 MAPK inhibitor Ralimetinib dimesylate (LY2228820), we performed cell viability, colony formation, apoptosis, and cell cycle analysis in ESCC cell lines. We provide novel pre-clinical evidence that inhibition of p38 MAPK signaling can augment the anti-tumor activity of an MDM2 antagonist in p53-mutant human tumor models of ESCC."

Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • MDM2 • TP53

P38 kinase as a therapeutic target to reverse an immune suppressive tumor microenvironment in metastatic breast cancer (SABCS 2021) - "We tested the migration of the monocyte-like cell line RAW 264.7 in response to tumor-conditioned media prepared from tumor cells treated with or without the p38 inhibitor, Ralimetinib. Our data showed that the migration of RAW 264.7 cells was significantly diminished towards the conditioned media from tumor cells treated with the p38 inhibitor or from tumor cells with a genetic inactivation of p38α by CRISPR/Cas9 compared to the corresponding controls. Altogether, our studies demonstrate that p38 kinase is a potential therapeutic target, which reshapes the immune suppressive contexture of TME in MBC to improve antitumor immunity."

Biomarker • IO biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • CD8 • ICOS • IRF8 • TNFRSF9

A randomized, double-blind, placebo-controlled phase Ib/II study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine (G) and carboplatin (C) versus GC for women with recurrent platinum-sensitive ovarian cancer. (ASCO 2019) - P1b/2; "Addition of ralimetinib to GC resulted in modest improvements in PFS. Grade 3/4 elevated ALT was more common in the ralimetinib arm. Clinical trial information: NCT01663857"

Clinical • P1/2 data