takinib (EDHS-206) / Duke University - LARVOL DELTA

Targeting tumor-intrinsic TAK1 triggers anti-tumor immunity and sensitizes pancreatic cancer to checkpoint blockade. (PubMed, bioRxiv) - "Pharmacological inhibition of TAK1 with Takinib, or genetic deletion of MAP3K7 in autochthonous p48-Cre;TP53 flox/flox ;LSL-KRAS G12D GEMM, enhances intratumoral CD4 + and CD8 + effector T cell infiltration and renders immune checkpoint blockade (ICB) effective...At the molecular level, TAK1 phosphorylates Ephrin Receptor A2 (EphA2) at Serine 897, which in turn phosphorylates RAD51 at Tyrosine 315, a key DNA repair protein involved in homologous recombination. We uncover TAK1 as a critical mediator in maintaining genomic integrity and highlights its potential as a therapeutic target to induce an inflamed TME that sensitizes PDAC to ICB."

Checkpoint inhibition • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8 • CGAS • KRAS • MAP3K7 • RAD51 • STING • TGFB1 • TP53

TAK1 blockade induces DNA damage and immunogenic cGAS–STING pathway activation in pancreatic cancer (SITC 2025) - "Pharmacological inhibition of TAK1 with Takinib, or genetic deletion of MAP3K7 in autochthonous p48-Cre; TP53flox/flox; LSL-KRASG12D GEMM, enhances intratumoral CD4+ and CD8+ effector T cell infiltration and renders immune checkpoint blockade (ICB) effective. Mechanistically, TAK1 inhibition induces DNA damage and cytoplasmic DNA leakage, which activates the cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) DNA sensing pathway, triggering inflammatory responses that promote adaptive immune cell infiltration. At the molecular level, TAK1 phosphorylates Ephrin Receptor A2 (EphA2) at Serine 897, which in turn phosphorylates RAD51 at Tyrosine 315, a key DNA repair protein involved in homologous recombination.Conclusions We uncover TAK1 as a critical mediator in maintaining genomic integrity and highlights its potential as a therapeutic target to induce an inflamed TME that sensitizes PDAC to ICB."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8 • CGAS • KRAS • MAP3K7 • RAD51 • STING • TGFB1

TAK1 blockade induces DNA damage and immunogenic cGAS–STING pathway activation in pancreatic cancer (AACR-NCI-EORTC 2025) - "Pharmacological inhibition of TAK1 with Takinib, or genetic deletion of MAP3K7 in autochthonous p48-Cre; TP53flox/flox; LSL-KRASG12D GEMM, enhances intratumoral CD4+ and CD8+ effector T cell infiltration and renders immune checkpoint blockade (ICB) effective. We uncover TAK1 as a critical mediator in maintaining genomic integrity and highlights its potential as a therapeutic target to induce an inflamed TME that sensitizes PDAC to ICB."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8 • CGAS • KRAS • MAP3K7 • RAD51 • STING • TGFB1

A Dual Inhibitor of TAK1 and MAP4K2, NG25, Suppresses Cytokine-driven Inflammation in Juvenile Idiopathic Arthritis Synovial Fibroblasts (ACR Convergence 2025) - "The efficacy of NG25 was further compared with different TAK1 inhibitors (5Z-7-oxozeaenol (5Z), takinib, or HS-276). Our preliminary findings delineate NG25's potential anti-inflammatory and anti-chemotactic activities in JIASFs. These findings lay a foundation for testing the efficacy of NG25 in animal models of JIA."

Idiopathic Arthritis • Immunology • Inflammation • Rheumatology • CDH11 • CXCL5 • CXCL8 • ICAM1 • IFNG • IL1B • IL6 • LY6G6D • MMP3 • PDPN • PTGS2 • TNFA • VCAM1

TAK1 blockade induces DNA damage and immunogenic cGAS–STING pathway activation in pancreatic cancer Free (AACRPanCa 2025) - "Inhibiting TAK1 pharmacologically (with Takinib) or genetically in autochthonous PDAC mice enhances T cell infiltration, reduces immunosuppressive macrophages, and sensitizes tumors to immune checkpoint blockade (ICB)...Mechanistically, we found that TAK1 phosphorylates EphA2 (Ser897), which in turn phosphorylates RAD51 (Tyr315), a critical driver of homologous recombination repair. Our findings reveal a novel role for TAK1 in maintaining genomic integrity and underscore its therapeutic potential in reprogramming the TME to sensitize PDAC to ICB."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • HRD • MAP3K7 • RAD51 • TGFB1

Emodin Alleviates Monocrotaline-Induced Pulmonary Arterial Hypertension by Directly Targeting TAK1. (PubMed, Drug Des Devel Ther) - "The indispensable role of TAK1 in mediating emodin's effects was corroborated through pharmacological blockade with Takinib, a highly potent and selective TAK1 inhibitor. The experiment has demonstrated for the first time that emodin directly targets TAK1, downregulates the expression of IL-17A, IL-17RA, and Phospho-TAK1, blocks the activation of the IL-17 signaling pathway, inhibits PASMCs proliferation, and alleviates PAH. This study provides a theoretical basis for the clinical application of emodin."

Journal • Cardiovascular • Hypertension • Pneumonia • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • IL17A • IL17RA • MAP2K3

Takinib exhibits antitumor effects in NF1-associated plexiform neurofibroma via NF-κB pathway inhibition (ESDR 2025) - "Selumetinib, a MEK inhibitor, has been approved for treating plexiform neurofibromas (PN) in patients with neurofibromatosis type 1 (NF1), but some clinical cases of resistance have been reported. To explore the molecular mechanism of this variability, we conducted RNA sequencing to compare gene expression profiles between Takinib-sensitive and -resistant cell lines and identified candidate genes potentially involved in Takinib-induced antitumor effects. These findings suggest that the NF-κB pathway contributes to PN cell proliferation and highlight the need for further research into alternative therapeutic strategies targeting this pathway."

Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • NF1

Investigating The Effect of Two TAK1 Inhibitors on an Ovarian Granulosa Cell Tumor-Derived Cell Line (ENDO 2025) - "Transcriptomic analysis suggests that takinib exhibits greater specificity for TAK1. These findings underscore the potential of TAK1 inhibition as a therapeutic approach for aGCT."

Preclinical • Oncology • Ovarian Cancer • Solid Tumor • CASP3 • CASP7 • FOXL2 • XIAP

EXPRESS: TLR3 mediates central sensitization in a chronic migraine model induced by repeated nitroglycerin through the ERK signaling pathway. (PubMed, Mol Pain) - "In addition, we investigated the effects of TLR3 inhibitor(CU CPT4a), MEK inhibitor(PD98059), TRAF6 inhibitor(C25-140), and TAK1 inhibitor (Takinib) on chronic migraine-like behavior, and activation of the ERK pathway in the Trigeminal nucleus caudalis(TNC). Concurrent inhibition of TLR3 function, TRAF6, TAK1, and the ERK pathway counteracted these changes and alleviated hyperalgesia in CM mice. Con-clusions: Our findings suggest that TLR3 may play a role in central sensitization in CM mice by TRAF6-TAK1 axis modulating the ERK signaling pathway."

IO biomarker • Journal • CNS Disorders • Migraine • Neuralgia • Pain • FOS • TLR3 • TRAF6

Targeting TAK1 kinase triggers anti-tumor immunity and sensitizes pancreatic cancer to checkpoint blockade (AACR 2025) - "The pharmacological inhibition of the TAK1 using selective TAK1 inhibitor Takinib significancy reduces tumor progression, prolong overall survival, enhances intratumoral CD4+ and CD8+ effector T cells, and decreases myeloid infiltration in the p48-Cre/TP53f/f/LSL-KRASG12D (KPC) mouse PDAC model...Mechanistically, inhibition of TAK1 in PDAC cells triggers cGAS-STING signaling by inducing cytosolic DNA damage which facilitates cytotoxic CD8+ T cell-dependent cell death. Together, our data provide the rationale for combining TAK1 inhibition with immune checkpoint blockade (anti-PD-1 and anti-CTLA4) as a therapeutic strategy for PDAC patients."

Checkpoint block • Checkpoint inhibition • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8 • KRAS • MAP3K7 • TGFB1

Senescent retinal pigment epithelial cells promote angiogenesis in choroidal neovascularization via the TAK1/p38 MAPK pathway. (PubMed, Exp Eye Res) - "Consistently, we found that the TAK1 inhibitors 5Z-7-oxozeaenol and takinib reversed the effects of conditioned media from senescent ARPE-19 cells on the wound healing, migration, survival, and tube formation abilities of HUVECs...Thus, senescent RPE cells may promote angiogenesis via the TAK1/p38 MAPK pathway. Further, inhibiting TAK1 expression alleviates pathological neovascularization and improves retinal function in a laser-induced CNV rat model, highlighting the therapeutic potential of this approach for treating nAMD."

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

Dexamethasone's Clinical Efficacy in Experimental Autoimmune Pancreatitis Correlates with a Unique Transcriptomic Signature, Whilst Kinase Inhibitors Are Not Effective. (PubMed, Biomedicines) - "(4) Dexamethasone effectively reduced AIP severity, while takinib and tofacitinib were ineffective. The unique gene expression profile in dexamethasone-treated mice may provide a basis for identifying new drug targets for AIP treatment."

Journal • Fibrosis • Immunology • Inflammation • Pancreatitis • CD69 • CD8 • FOXP3 • IL2RA

Impact of Combination Therapy with Chemical Drugs and Megavoltage X-ray Exposure on Breast Cancer Stem Cells' Viability and Proliferation of MCF-7 and MDA-MB-231 Cell Lines. (PubMed, Curr Pharm Des) - "Anti-cancer and cytotoxic effects of metformin can be effective in this strategy. In conclusion, the combination of conventional chemotherapeutic drugs, including SB203580, metformin, and takinib with X-ray exposure can be a new approach to diminish the drug resistance of breast cancer."

Cancer stem • Combination therapy • Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • CXCR4

Neuroprotective effects of takinib on an experimental traumatic brain injury rat model via inhibition of transforming growth factor beta-activated kinase 1. (PubMed, Heliyon) - "As a result, an enhancement of neuronal function and survival was observed post-TBI. These findings highlight the medicinal value of Takinib in the management of TBI and offer an experimental justification for further investigation of TAK1 as a potential pharmacological target."

Journal • Preclinical • CNS Disorders • Inflammation • Oncology • Vascular Neurology • CASP3 • CLDN5 • IL1B • TJP1 • TNFA

Discovery of imidazo[1,2-b]pyridazine-containing TAK1 kinase inhibitors with excellent activities against multiple myeloma. (PubMed, RSC Med Chem) - "Under similar conditions, the known TAK1 inhibitor, takinib, inhibits the kinase with an IC of 187 nM. Compound 26 and analogs thereof inhibit the growth of multiple myeloma cell lines MPC-11 and H929 with GI values as low as 30 nM. These compounds have the potential to be translated into anti-MM therapeutics."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Upregulation of TRIM16 mitigates doxorubicin-induced cardiotoxicity by modulating TAK1 and YAP/Nrf2 pathways in mice. (PubMed, Biochem Pharmacol) - "The clinic application of doxorubicin (DOX) is severely limited by its severe cardiotoxicity. This effect was nullified by siTRIM16 or TAK1 inhibitor Takinib. Collectively, the current study elaborates that upregulating TRIM16 mitigates DOX-induced cardiotoxicity through anti-inflammation and anti-oxidative stress by modulating TAK1-mediated p38 and JNK as well as YAP/Nrf2 pathways, and targeting TRIM16 may provide a novel strategy to treat DOX-induced cardiotoxicity."

Journal • Preclinical • Cardiovascular • Fibrosis • Immunology • Inflammation • Targeted Protein Degradation • NFE2L2 • TRIM16 • YAP1

Takinib inhibits microglial M1 polarization and oxidative damage after subarachnoid hemorrhage by targeting TAK1-dependent NLRP3 inflammasome signaling pathway. (PubMed, Front Immunol) - "In general, our study demonstrated that takinib could protect against EBI by targeting TAK1-ROS-NLRP3 inflammasome signaling. Inhibition of TAK1 might be a promising option in the management of SAH."

Journal • CNS Disorders • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology • NLRP3

Chronic treatment with TNF-α, alone and in combination with Takinib, SB203580 and metformin induce cell death in breast cancer. (PubMed, Heliyon) - "Although, in MCF-7 cells only combination of TNF-α and Takinib reduced BCSCs population in a time dependent manner. Altogether, we showed that TNF-α alone or in combination with other treatments can affect the progression of breast cancer."

Combination therapy • Journal • Breast Cancer • Oncology • Solid Tumor • CD24 • CD44 • CXCR4 • TNFA

TAK1 Reduces Surgery-induced Overactivation of RIPK1 to Relieve Neuroinflammation and Cognitive Dysfunction in Aged Rats. (PubMed, Neurochem Res) - "Ageing-related decreases in TAK1 expression may contribute to surgery-induced RIPK1 overactivation, resulting in neuroinflammation and cognitive impairment in old rats."

Journal • Preclinical • Surgery • Alzheimer's Disease • Anesthesia • CNS Disorders • Cognitive Disorders • Inflammation • IL1B • NF-κβ • RIPK1 • TNFA

Transforming growth factor-β-activated kinase 1 (TAK1) mediates chronic pain and cytokine production in mouse models of inflammatory, neuropathic, and primary pain. (PubMed, J Pain) - "Here, we evaluated the ability of our TAK1 small molecule inhibitor, takinib, to attenuate pain and inflammation in pre-clinical models of inflammatory, neuropathic, and primary pain...PERSPECTIVE: This article reports the therapeutic potential of TAK1 inhibitors for the treatment of chronic pain. This new treatment has the potential to provide a greater therapeutic offering to physicians and patients suffering from chronic pain as well as reduce the dependency on opioid based pain treatments."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Immunology • Inflammation • Musculoskeletal Pain • Neuralgia • Oncology • Pain • TNFA

Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis. (PubMed, ACS Chem Biol) - "As a result, patients often return to more problematic therapies such as methotrexate or hydroxychloroquine, which carry long-term side effects...Using a directed medicinal chemistry approach, driven by the cocrystal structure of the TAK1 inhibitor takinib, we developed HS-276, a potent (K = 2.5 nM) and highly selective orally bioavailable TAK1 inhibitor...The in vitro and in vivo efficacy of HS-276 showed significant inhibition of TNF-mediated cytokine profiles, correlating with significant attenuation of arthritic-like symptoms in the CIA mouse model of inflammatory RA. Our studies reinforce the hypothesis that TAK1 can be safely targeted pharmacologically to provide an effective alternative to frontline biologic-based RA therapeutics."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway. (PubMed, Int J Mol Sci) - "In THP-1 monocyte-derived macrophages, takinib again led to the lipopolysaccharide-induced phosphorylation of TAK1 without a marked inhibition of the TAK1 downstream effectors, namely, of c-Jun N-terminal kinase (JNK), phospho-c-Jun, NF-κB phospho-p65 or phospho-IκBα. Taken together, these findings indicate that takinib inhibits inflammation in these cells by targeting multiple signaling pathways, most notably the JAK/STAT pathway in human RASFs."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • IL1B • MAPK8 • TGFB1

[VIRTUAL] Takinib Inhibits IL-1β-Induced Activation of Signal Transducer and Activator of Transcription 3 (STAT3) in Human Rheumatoid Arthritis Synovial Fibroblasts (ACR-CONVERGENCE 2021) - "Our findings suggest STAT3 is an important target of takinib in the IL-1β signaling pathway, which may further be utilized for therapeutic purposes."

Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CCL2 • CXCL5 • CXCL8 • IL1B • IL6 • STAT3 • TGFB1 • TNFA

[VIRTUAL] Canonical TGF-β Signaling Mediates Renal Tubule Epithelial Cell Differentiation In Vitro (KIDNEY WEEK 2021) - "After two weeks in culture, cells were supplemented with TGFβ receptor I (TβR1) inhibitors SB431542 or A8301, Smad3 inhibitor SIS3, PI3K inhibitor LY294002, Rapamycin, p38 MAPK inhibitor SB203580, Takinib (2nM), Trametinib. Data are mean ± SEM (n=4). *p<0.05, **p<0.01, ***p<0.001."

Preclinical • SMAD3 • TGFB1

Effects of NF-kB Signaling Inhibitors on Bed Bug Resistance to Orally Provisioned Entomopathogenic Bacteria. (PubMed, Insects) - "In the present study, we administered four small molecule inhibitors of NF-kB signaling (BMS345541, IKK16, IMD0354, Takinib) to bed bugs by feeding them in a blood meal. Enhanced mortality was independent of direct effects of IKK16 on P. entomophila growth in vitro but was associated with higher bacterial loads in vivo (i.e., reduced resistance). Together, these results provide new insight into the regulation of the bed bug immune system and suggest that administration of entomopathogens in combination with inhibition of immune signaling pathways to reduce infection resistance may be effective for biological control of bed bugs."

Journal • Immunology