napabucasin (BBI608) / Sumitomo Pharma - LARVOL DELTA

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

Exploring EHMT2 modulation by niclosamide in esophageal squamous cell carcinoma (ESMO Asia 2024) - "In vitro studies demonstrated increased Niclosamide sensitivity in metastatic daughter cell lines and dose-dependent downregulation of EHMT2 RNA and protein levels post-Niclosamide treatment, with LC3II induction unaffected by chloroquine or MG132 co-treatment...Furthermore, the suppression of EHMT2 by Niclosamide involve both STAT3 and c-Myc pathways, as indicated by the use of specific inhibitors BBI-608 and 10058-F4. TCGA data revealed poorer overall survival rates in ESCC patients with high EHMT2 and c-Myc expression (p=0.026), though no significant differences in progression-free survival were observed (p=0.78). Conclusions Our combined in silico and in vitro findings propose EHMT2 as a potential epigenetic regulator under the STAT3 and c-Myc axis in ESCC, warranting further exploration and validation in vivo and clinically."

Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • EHMT2 • MYC

Design, synthesis, and biological evaluation of novel (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl) derivatives as potent STAT3-targeting anticolorectal cancer agents. (PubMed, Bioorg Chem) - "In vivo studies confirmed significant tumour-suppressive effects upon oral administration of NW16 along with favourable tolerability in a colorectal cancer xenograft model. These results indicate that NW16 could be a promising candidate for developing targeted therapy for colorectal cancer because of its multifaceted mechanism."

Journal • Colorectal Cancer • Oncology • Solid Tumor • STAT3

Probing the Depths of Molecular Complexity: STAT3 as a Key Architect in Colorectal Cancer Pathogenesis. (PubMed, Curr Gene Ther) - "For example, imatinib acts by targeting cell surface receptors, and these inhibitors have shown potential for the control and treatment of tumor growth, angiogenesis, and metastasis. Imatinib, for example acts by targeting cell surface receptors, and these inhibitors have shown the future direction toward the control and treatment of tumor growth, angiogenesis, and metastasis."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • STAT3

Structure, function, signaling pathways and clinical therapeutics: The translational potential of STAT3 as a target for cancer therapy. (PubMed, Biochim Biophys Acta Rev Cancer) - "Some of them such as TTI101 and BBI608 have been approved by the FDA for the treatment of certain cancers. All in all, STAT3 plays an important role in cancer progression and becomes a potential target for cancer treatment."

Journal • Review • Oncology • STAT3

Napabucasin Inhibits Proliferation and Migration of Glioblastoma Cells (U87) by Regulating JAK2/STAT3 Signaling Pathway. (PubMed, Medicina (Kaunas)) - "In this study, the anti-proliferative and apoptotic effects of NP and the chemotherapy agent doxorubicin (DX), a natural compound, on glioblastoma cells (U87) were investigated. Since it can suppress Jak2/Stat3, an important cancer cell proliferation pathway in glioblastoma, the combination of NP and DX can be used as an alternative treatment agent. But no synergistic effect of NP and DX on the U87 cells of the glioblastoma cell line was observed."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • JAK2

Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma. (PubMed, Neuro Oncol) - "As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB."

Journal • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • NQO1

Effect of napabucasin and doxorubicin via the Jak2/Stat3 signaling pathway in suppressing the proliferation of neuroblastoma cells. (PubMed, Acta Cir Bras) - "NP showed that it suppresses the proliferation of neuroblastoma cells. Due to its inhibitory effect on Jak2 and Stat3, it can be used to prevent invasion of SH-SY5Y cells. NP, which can inactivate Jak2/Stat3, can be used as a treatment agent by combining with DX in proliferation pathway in neuroblastoma."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • IL6

CONVECTION ENHANCED DRUG DELIVERY AND RADIOSENSITIZATION FOR DIFFUSE MIDLINE GLIOMA (SIOP 2024) - "In our orthotopic DMG mouse model, combination RT and CED of Napabucasin led to a significant OS benefit when compared to monotherapy (median OS 46 days with combination treatment, 33 days with RT monotherapy, and 26 days with Napabucasin monotherapy, p<0.001).Conclusions In this study, we identify Napabucasin as a promising radiosensitizer in DMG. Furthermore, this is the first preclinical study showing safety/efficacy of CED with concurrent RT in DMG."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • NQO1

Convection-Enhanced Drug Delivery and Radiosensitization for Diffuse Midline Glioma (ASTRO 2024) - "In this study, we identify Napabucasin as a promising radiosensitizer in DMG. Furthermore, this is the first preclinical study showing safety/efficacy of CED with concurrent RT in DMG. As RT is the cornerstone of DMG care, identifying novel radiosensitizing techniques in this devastating disease is paramount to clinical success."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • NQO1