napabucasin (BBI608) / Sumitomo Pharma - LARVOL DELTA

BBI608 induces apoptosis in mucoepidermoid carcinoma cells by targeting a post-transcriptional regulatory mechanisms of myeloid cell leukemia-1. (PubMed, Arch Oral Biol) - "These findings demonstrate that BBI608 effectively inhibits MEC cell proliferation in vitro by inducing Mcl-1-dependent apoptosis. This suggests BBI608 warrants further investigation as a potential therapeutic agent for MEC."

Journal • Hematological Malignancies • Leukemia • Oncology • Salivary Gland Cancer • Squamous Cell Carcinoma • Targeted Protein Degradation • ANXA5 • CASP3 • MCL1

Discovery of a novel napabucasin derivative B16 as a potent STAT3 inhibitor for the treatment of triple-negative breast cancer. (PubMed, Eur J Med Chem) - "In vivo, B16 (10 mg/kg) reduced tumor volume by 82 % in a MDA-MB-231 xenograft model, outperforming napabucasin (50 % reduction in tumor volume), with no significant toxicity observed. These findings established B16 as a highly potent STAT3 inhibitor, offering a promising therapeutic strategy for TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Comparative Efficacy and Safety of Chemotherapeutic, Targeted, and Immunotherapy Drugs for Pancreatic Ductal Adenocarcinoma Treatment: A Network Meta-Analysis of RCTs (ACG 2025) - "Our analysis included 33 RCTs with a total sample size of 9,239 participants, comprising 5,636 in the treatment group and 3,603 in the control group. The included studies evaluated therapies such as Atezolizumab (79), Cabozantinib (76), Combined Chemotherapy (58), Demivistat + FOLFIRINOX (266), Durvalumab (3), EGPH20 + GEM-NABP (327), Erlotinib (518), FOLFIRINOX (433), Gemcitabine (2,090), Irinotecan (1,216), Mitazalimab (70), Nab-Paclitaxel (71), Nadunolimab (76), Napabucasin + GEM-NABP (565), Olaparib (124), Narilifox (766), Placebo (322), and Zenocutumab (454). The most significant survival benefit was observed with Irinotecan (OR = 4.96, 95% CI [1.45; 16.91],), while the least survival benefit was seen with Zenocutumab (OR = 0.38, 95% CI [0.03; 4.41],) compared to placebo."

Retrospective data • Novel Coronavirus Disease • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Synergistic MDM2-STAT3 Inhibition Demonstrates Strong Anti-Leukemic Efficacy in Acute Lymphoblastic Leukemia. (PubMed, Int J Mol Sci) - "In this study, human ALL cell lines-characterized by either wild-type or mutant tumor protein p53 (TP53) status-were treated with RG7388 (an MDM2 (mouse double minute 2 homolog) inhibitor) and BBI608 (a STAT3 (signal transducer and activator of transcription 3) inhibitor), both as single agents and in combination. This combinatorial approach augments apoptosis and tumor growth suppression, offering a promising avenue for expanding treatment options for a broader patient population. Further investigation is warranted to validate these preclinical findings and to explore translational implications in genetically diverse ALL subsets."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

2-oxoglutarate:acceptor oxidoreductase-catalyzed redox cycling effectively targets coccoid forms of Helicobacter pylori. (PubMed, Nat Commun) - "Structural, biochemical, and microbiological analyses identify Leu44 and Lys46 within the OorD subunit as critical residues for napabucasin recognition and catalysis. These findings establish OOR-mediated redox cycling as a robust antimicrobial strategy that sustains endogenous ROS production to combat refractory H. pylori infections."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Oncology • Peptic Ulcer • Solid Tumor

Brigimadlin (BI-907828) and napabucasin (BBI608) cooperatively trigger apoptosis in chronic lymphocytic leukemia cells by simultaneous iİnhibition of MDM2 and STAT3. (PubMed, Mol Biol Rep) - "These findings establish a mechanistic rationale for the concurrent targeting of the MDM2 and STAT3 axes and provide preclinical evidence for a promising, non-genotoxic therapeutic strategy in p53-functional CLL. A limitation of this study is the lack of in vivo validation and clinical data, which are necessary to further assess the safety, optimal dosing, and efficacy, particularly in elderly or unfit patients with limited treatment options."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CASP3 • CASP7 • CDKN1A • STAT3

Discovery of Juglone Derivatives as Novel STAT3 Inhibitors with Potent Suppression of Cancer Cell Stemness against Breast Cancer. (PubMed, J Med Chem) - "YZ-35 exhibited remarkable antiproliferative activity across multiple breast cancer cell lines and selectively suppressed BCSC self-renewal, outperforming TTI-101 and matching BBI-608 in potency. In vivo, YZ-35 achieved approximately 90% tumor growth inhibition (10 mg/kg) in xenograft models, with reduced toxicity versus paclitaxel. Mechanistic studies confirmed STAT3 pathway disruption and BCSC depletion. These results highlight YZ-35 as a natural product-derived STAT3 inhibitor with dual antitumor and anti-CSC activity, offering a translational strategy for refractory BRCA."

Journal • Breast Cancer • Oncology • Solid Tumor • BRCA

Integrated analysis of CD30 detection methodologies and synergistic drug combinations for optimizing brentuximab vedotin therapy in lymphoma. (PubMed, Clin Exp Med) - "Brentuximab vedotin (BV), a CD30-targeted antibody-drug conjugate, has shown significant efficacy in CD30-positive lymphoma. To address this, we conducted high-throughput screening (HTS) and identified auranofin and napabucasin as synergistic agents that enhance the efficacy of BV. These findings not only highlight the advantages of FCM for CD30 detection, but also provide valuable insights into combination strategies to optimize the therapeutic potential of BV."

Journal • Hematological Malignancies • Lymphoma • Oncology • TNFRSF8

In vitro assessment of BBI608 in 2D and 3D culture models for drug repositioning in oral squamous cell carcinoma. (PubMed, Oncol Rep) - "Consistent with the results from 2D culture, BBI608 showed effective anticancer effects against OSCC spheroids in 3D culture. These results suggest that BBI608 effectively inhibits STAT3 activation in both 2D and 3D models, offering a promising therapeutic strategy and supporting its potential for repurposing in patients with OSCC who exhibit elevated STAT3 activity."

Journal • Preclinical • Hematological Malignancies • Leukemia • Oncology • Oral Cancer • Squamous Cell Carcinoma • ANXA5 • BIRC5 • CASP3 • MCL1

STAT3 Inhibition Prevents Adaptive Resistance and Augments Nature Killer (NK) Cell Cytotoxicity to KRASG12C Inhibitors in Non-Small Cell Lung Cancer (NSCLC) (ATS 2025) - "Through high-throughput screening of a customized pharmacological library containing 423 compounds, we identified napabucasin, a signal transducer and activator of transcription 3 (STAT3) inhibitor, synergistically potentiated KRASG12C inhibitor sotorasib-induced growth inhibition both in sensitive and resistant KRASG12C NSCLC cell lines. Our study dissected an unknown mechanism of adaptive resistance of KRASG12C inhibitors, with the STAT3 activation not only sustaining the regrowth of tumor cells under KRAS inhibition but also up-regulating HLA-B transcription to dampen the cytotoxicity of infiltrated NK cells. Together, these studies identified a promising combinational therapeutic strategy for KRASG12C-mutant NSCLC and demonstrated STAT3 activation as a pivotal mediator of adaptive resistance for KRASG12C inhibitors, implying the altered STAT3 phosphorylation levels under treatment as the predictive biomarker of sensitivity."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HLA-B • KRAS

Effect of ponatinib on the metabolism of cariprazine in vitro and in vivo and the underlying mechanism. (PubMed, Toxicol Appl Pharmacol) - "The objective of the present study was to examine the inhibitory impacts of three antitumor drugs (olmutinib, napabucasin and ponatinib) on the metabolism of cariprazine, and the molecular docking of cariprazine and ponatinib in relation to CYP3A4 was also evaluated. Molecular docking studies had demonstrated that both cariprazine and ponatinib could engage in hydrophobic interactions with residue PHE-304 on CYP3A4. Consequently, when ponatinib is employed in conjunction with cariprazine in a clinical setting, it is imperative to assess the efficacy and adverse effects, and adjust the dosage to attain the optimal efficacy."

Journal • Preclinical • CNS Disorders • Mental Retardation • Oncology • Psychiatry • Schizophrenia • CYP3A4

Targeting NAD(P)H: Quinone oxidoreductase 1 (NQO1) for colorectal cancer diagnosis and therapy (AACR 2025) - "Based on meta-analysis and a computational approach, NQO1 is a viable biomarker and a possible molecular target in CRC. In vitro, results showed that inhibiting NQO1 by BBI 608 decreased cell proliferation in both CRC cell lines. Knockout, overexpression, or site-directed mutagenesis is essential for a better understanding of BBI 608-targeted NQO1 and its amino acids."

Colorectal Cancer • Oncology • Solid Tumor • NQO1

Napabucasin analogues with increased bioavailability and efficacy in fibrolamellar hepatocellular carcinoma (AACR 2025) - "In FLC, a deletion of 400,000 base pairs occurs in a chromosome 19 copy, leading to the formation of a fusion protein comprising heat shock protein DNAJB1 and the catalytic subunit of Protein Kinase A (DNAJB1-PRKACA). Napabucasin is known to work in multiple signaling pathways and have been shown cytotoxic against both PDX and direct-from-patient FLC tumor cells. We anticipate that the organic synthesis and development of optimized Napabucasin analogues, along with the evaluation of their cytotoxicity and proliferation effectiveness compared to the parent compound, Napabucasin, will result in compounds with improved bioavailability and efficacy, particularly in FLC model cell lines (FLX1 and Huh7-Chimera)."

Clinical • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

Synergistic suppression of gemcitabine resistance in PDAC by targeting STAT3 and ABCB11 (AACR 2025) - "Cytotoxicity assays evaluated the sensitivity of resistant and non-resistant PDAC cells to gemcitabine, napabucasin, and an EGFR inhibitor (gefitinib). The combination of gemcitabine, napabucasin, and glibenclamide synergistically suppresses tumor growth in resistant models, highlighting a potential therapeutic strategy to overcome gemcitabine resistance. Further studies are warranted to optimize combination therapies for clinical application."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ABCB1 • STAT3

Photothermal treatment of prostate tumor with micellar indocyanine green and Napabucasin to co-ablate cancer cells and cancer stem cells. (PubMed, J Control Release) - "The tumor analyses demonstrated clear downregulation of CSC-related biomarkers such as OCT4, SOX2, CD133 and pSTAT3 as well as PSMA by Acupa-mICG-Nap. Rational formulated micellar indocyanine green and napabucasin plus NIR appears as an appealing strategy to co-ablate cancer cells and CSCs with rapid tumor de-bulking yet no recurrence."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD133 • POU5F1 • SOX2

Napabucasin targets resistant triple negative breast cancer through suppressing STAT3 and mitochondrial function. (PubMed, Cancer Chemother Pharmacol) - "In vivo, napabucasin significantly inhibited tumor growth in paclitaxel-resistant TNBC xenograft models and reduced the expression of proliferation marker Ki67 and phosphorylation of STAT3. These findings demonstrate that napabucasin effectively targets paclitaxel-resistant TNBC cells by impairing mitochondrial function and inhibiting key signaling pathways, providing a strong rationale for its further clinical investigation as a therapeutic agent to overcome chemoresistance in TBNC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • STAT3

Targeting stemness pathways modulates macrophage polarization and reprograms the tumor microenvironment. (PubMed, Front Immunol) - "We used four stemness inhibitors-salinomycin, SB-431542, JIB-04, and napabucasin-each targeting different pathways (Wnt/β-catenin, TGF-β, histone demethylation, and STAT3, respectively), to evaluate their effects on CMS4 CRC cell lines (HCT116 and SW620) and human peripheral blood-derived macrophages in an indirect co-culture model. Our study highlights the dual potential of stemness inhibitors to target both cancer cells and the immune microenvironment. These findings offer promising strategies for enhancing favorable immunomodulation in mesenchymal-like colorectal tumors."

Biomarker • Journal • Breast Cancer • Colorectal Cancer • Immunology • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD133 • CTNNB1 • STAT3 • TGFB1

Formosanin C inhibits triple-negative breast cancer progression by suppressing the phosphorylation of STAT3 and the polarization of M2 macrophages. (PubMed, Breast Cancer Res Treat) - "This study is the first to show that FC restrains the EMT of TNBC cells by obstructing the STAT3 pathway and hinders the M2 polarization of macrophages and immune evasion. Therefore, FC holds the possibility of being utilized as a therapeutic remedy for TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • STAT3

Crosstalk Between nNOS/NO and COX-2 Enhances Interferon-Gamma-Stimulated Melanoma Progression. (PubMed, Cancers (Basel)) - "Cotreatment with celecoxib effectively diminished these changes induced by PGE2...STAT3 inhibitor napabucasin also inhibited COX-2 expression both in the presence and absence of IFN-γ...HH044 treatment also significantly reduced tumor PGE2 levels in vivo. Our study demonstrates the positive feedback loop linking nNOS-mediated NO signaling to the COX-2/PGE2 signaling axis in melanoma, which further potentiates the pro-tumorigenic activity of IFN-γ."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • IFNG • PD-L1 • PTGS2

STAT3 Inhibition Prevents Adaptive Resistance and Augments NK Cell Cytotoxicity to KRASG12C Inhibitors in Nonsmall Cell Lung Cancer. (PubMed, Cancer Sci) - "A high-throughput screening of a pharmacological library with 423 compounds revealed that napabucasin, a signal transducer and activator of transcription 3 (STAT3) inhibitor, synergistically potentiated the growth inhibition effect of the KRASG12C inhibitor sotorasib in sensitive and resistant KRASG12C NSCLC cell lines. Moreover, we unveiled and verified the binding site of phosphorylated STAT3 at the HLA-B promoter, an inhibitor ligand for NK cells. Our study dissected an unknown mechanism of adaptive resistance to KRASG12C inhibitors, with the STAT3 activation sustaining the regrowth of tumor cells under KRAS inhibition and up-regulating HLA-B transcription to dampen the cytotoxicity of infiltrated NK cells."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HLA-B • KRAS

Discovery of naphthoquinone-furo-piperidone derivatives as dual targeting agents of STAT3 and NQO1 for the treatment of breast cancer. (PubMed, Eur J Med Chem) - "The anti-proliferative activity evaluation revealed that most of these compounds exhibited superior inhibitory activity against MDA-MB-231 and MDA-MB-468 breast cancer cell lines compared to napabucasin...Meanwhile, 16c showed encouraging anti-tumor efficacy in the MDA-MB-231 xenograft model. In summary, this protocol provides a new vision and new chemical entity for dual targeting STAT3 and NQO1."

Journal • Breast Cancer • Oncology • Solid Tumor • NQO1 • STAT3

Insights into IL-6/JAK/STAT3 signaling in the tumor microenvironment: Implications for cancer therapy. (PubMed, Cytokine Growth Factor Rev) - "Strategies include monoclonal antibodies against IL-6 or its receptor (e.g., Tocilizumab, Siltuximab), JAK inhibitors (e.g., Ruxolitinib), and STAT3-specific inhibitors (e.g., Napabucasin), which have exhibited promise in preclinical and initial clinical studies. Advances in biomarker-driven patient selection, RNA-based therapies, and isoform-specific inhibitors pave the way for more precise interventions. This review delves into the diverse roles of IL-6/JAK/STAT3 signaling in cancer progression, therapeutic strategies targeting this pathway, and the potential for integrating these approaches into personalized medicine to enhance treatment outcomes."

Biomarker • IO biomarker • Journal • Review • Oncology • CAFs • IL6

Exploring apoptotic pathways in SH-SY5Y neuroblastoma cells: combined effects of napabucasin and doxorubicin. (PubMed, Folia Morphol (Warsz)) - "As a results showed that NP and DX suppressed the proliferation of neuroblastoma cells and could do this through apoptotic pathways. NP can be used to suppress metastasis of SHSY-5Y cells as an inhibitor of the apoptosis pathway Bcl-2. It is thought that NP, which provides tumor suppression through an apoptotic mechanism, may be an alternative treatment agent in neurological cancers such as neuroblastoma."

IO biomarker • Journal • CNS Tumor • Genito-urinary Cancer • Neuroblastoma • Oncology • Solid Tumor • Urethral Cancer • BCL2 • CASP3 • STAT3

Genetic and microenvironmental evolution of colorectal liver metastases under chemotherapy. (PubMed, Cell Rep Med) - "Multi-omics and treatment response data from 115 samples of 49 patients with CRLM undergoing bevacizumab (BVZ)-based chemotherapy show little difference in genomic alterations in 92% of cases, while remarkable differences are observed at the transcriptomic level...Gene interference experiments suggest that SMAD4R361H/C mutations confer BVZ and 5-fluorouracil (5-FU) resistance through STAT3 signaling. Notably, supplementing BVZ and 5-FU with the STAT3 inhibitor GB201 restores therapeutic efficacy in SMAD4R361H/C cancer cells. Our study uncovers the evolutionary dynamics of CRLM and its microenvironment during treatment and offers strategies to overcome drug resistance."

Journal • Colorectal Cancer • Hepatology • Oncology • Solid Tumor • SMAD4

Napabucasin-loaded PLGA nanoparticles trigger anti-HCC immune responses by metabolic reprogramming of tumor-associated macrophages. (PubMed, J Transl Med) - "These findings demonstrated Napabucasin-PLGA NPs is a potential therapeutic candidate for HCC, and provided a new theoretical and experimental basis for further development and clinical application of Napabucasin."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • ANXA5