NT-157 / Purple Biotech - LARVOL DELTA

Machine learning approach identifies targeting strategy for selective AML dependency (ASH 2025) - "We focused our following analyses on positive regulators of IRF2BP2 expression as theirdecreased expression is predicted to decrease IRF2BP2 expression, subsequently inducing thebiologically relevant phenotype of AML cell specific cell death.Among the top candidates, insulin receptor substrate 2 (IRS2) emerged as a robust positive regulator ofIRF2BP2, thus predicting that reduced expression of IRS2 should lead to decreased IRF2BP2 expression.To test our model, we treated AML cell lines and patient derived AML cells with NT157, a selective IRS1/2inhibitor, known to decrease IRS2 expression...Importantly, the experimental validation of onepredicted regulator underlines the biological relevance of our computational strategy. This approach mayfacilitate the discovery of therapeutic entry points for biologically hard to characterize or otherwiseintractable targets across diverse biological contexts."

Machine learning • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CD34 • IRF2 • IRS2

Emerging role of HIC1 in prostate cancer progression and therapeutic response: A novel perspective. (PubMed, J Cell Commun Signal) - "Conversely, AR and IRS2 inhibitors like EPI-7170 and NT157 negatively affected PCa progression. These results underscore HIC1's potential as a therapeutic target in PCa, offering new insights into its role in cancer biology and treatment."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CASP3 • HIC1 • IRS2

TXNIP participates in the pathogenesis of PCOS by regulating glycolysis in granulosa cells. (PubMed, Biochem Biophys Res Commun) - "Additionally, treatment with the IRS-1 inhibitor NT157 confirmed that TXNIP regulates glycolysis in GCs through the IRS-1/PI3K signaling axis. This study is the first to demonstrate that TXNIP contributes to glycolytic dysfunction in PCOS GCs via the IRS-1/PI3K pathway, highlighting a potential target for PCOS diagnosis and therapy."

Journal • Endocrine Disorders • Polycystic Ovary Syndrome • PFKM • PKM • TXNIP

A heterodimer of hemoglobin identifies theranostic targets on brain-metastasizing melanoma cells. (PubMed, Int J Cancer) - "Among the top enriched functions of differentially expressed genes identified by RNAseq of BRIRi-treated versus control BMMC, TNF and apoptotic signaling pathways were observed. We propose that co-targeting BRD4 and IRS2 offers a promising approach for treating BMMC."

Journal • CNS Tumor • Melanoma • Neuroblastoma • Oncology • Solid Tumor • BRD4 • IRS2

Cancer-associated fibroblasts promote the progression and chemoresistance of HCC by inducing IGF-1. (PubMed, Cell Signal) - "Inhibition of IGF-1R also enhanced the therapeutic effect of sorafenib on HCC, especially chemoresistant tumours. STATEMENT OF SIGNIFICANCE: Our study showed IL-6-IGF-1 axis played crucial roles in the crosstalk between HCC and CAFs, providing NT157 inhibited of STAT3 and IGF-1R as a new targeted therapy in combination with sorafenib."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CAFs • IGF1 • IL6

Schwann Cells IGF-1 receptor intracellular signaling promotes an endothelial nitric oxide synthase-mediated Transient receptor potential ankyrin 1 (TRPA1) activation (EACR 2024) - "The IGF-1 effect was measured also in the presence of antagonists of IGF-1 receptor (IGF1-R) (PPP) and TRPA1 (A967079) receptors and inhibitors of: the IRS-1 (NT157), the Akt (Akti-1/2), eNOS (L-NAME) and a NO scavenger (cPTIO). The ensuing IGF-1R activation in SCs promotes an eNOS-mediated TRPA1 activation and release of reactive oxygen species that targets SC TRPA1. Glial cell-selective targeting of the various mediators that sustain cascade signals initiated by SC IGF-1R activation could be a promising area for future treatments against MBCP."

Breast Cancer • Immunology • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor • IGF1 • NOS3 • TRPA1

NT157 exhibits antineoplastic effects by targeting IRS and STAT3/5 signaling in multiple myeloma. (PubMed, Hematol Transfus Cell Ther) - "In summary, our study demonstrates that the IGF1/IGF1R/IRS signaling axis is differentially activated in MM cells and the NT157's capacity to modulate crucial molecular targets, promoting antiproliferative effects and apoptosis in MM cells. NT157 may offer a multifaceted approach to enhance MM therapy."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • IGF1 • IGF1R • IRS2 • RPS6 • STAT3 • STAT5

ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation. (PubMed, NPJ Breast Cancer) - "Of these, IRS1 stood out as a gene of interest, and ERα and PR occupancy at chromatin binding sites along IRS1 were uniquely altered in the context of ERα Y537S. Furthermore, siRNA knockdown of IRS1 or treatment with the IRS1 inhibitor NT-157 had a significant anti-proliferative effect in ERα Y537S cell lines, implicating IRS1 as a potential therapeutic target for restoring treatment sensitivity to patients with breast cancers harboring ERα Y537S mutations."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • PGR

Dendrobium officinale polysaccharide decreases podocyte injury in diabetic nephropathy by regulating IRS-1/AKT signal and promoting mitophagy. (PubMed, Aging (Albany NY)) - "DOP alleviates HG-induced podocyte injuryby regulating IRS-1/AKT signal and promoting mitophagy."

Journal • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • NPHS1

Insulin-induced long-term potentiation in the dentate gyrus of hippocampal formation. (PubMed, Psychoneuroendocrinology) - "The slope of field excitatory postsynaptic potentials (fEPSPs) and the amplitude of population spike (PS) were measured 15 min after a 60-min infusion of insulin (500 nM), NT157 (an IRS inhibitor, 6 μM), alone or together, or physiological saline...The results obtained provide a mechanistic link between insulin and synaptic plasticity. We concluded that insulin not only functions as a modulator of synaptic plasticity but also acts as a chemical inducer of LTP."

Journal • Anesthesia

LINC00638 promotes the progression of non-small cell lung cancer by regulating the miR-541-3p/IRS1/PI3K/Akt axis. (PubMed, Heliyon) - "Repressing IRS1/2 using its inhibitor NT157 repressed LINC00638-mediated oncogenic effects. LINC00638 may function as an oncogene in NSCLC by modulating the miR-541-3p/IRS1/PI3K/Akt axis."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IRS1

Regulation of erythroid differentiation in K562 cells by the EPAS1-IRS2 axis under hypoxic conditions. (PubMed, Front Cell Dev Biol) - "Therefore, we used an in vitro model of erythropoiesis generated from K562 cells transduced with shEPAS1 at 5% O in the presence or absence of the IRS2 inhibitor NT157...Intriguingly, inhibition of IRS2 could impair the progression of hypoxia-induced erythropoiesis without affecting EPAS1 expression. These findings indicated that the EPAS1-IRS2 axis may be a crucial pathway that regulates erythropoiesis and that drugs targeting this pathway may become promising agents for promoting erythroid differentiation."

Journal • EPAS1 • IRS2

Inhibition of LAR attenuates neuroinflammation through RhoA/IRS-1/Akt signaling pathway after intracerebral hemorrhage in mice. (PubMed, J Cereb Blood Flow Metab) - "ELP decreased RhoA and phosphorylated serine-IRS1, increased phosphorylated tyrosine-IRS1 and p-Akt, and attenuated neuroinflammation after ICH, which was reversed by LAR activating-CRISPR or NT-157. In conclusion, this study demonstrated that LAR contributed to neuroinflammation after ICH via RhoA/IRS-1 pathway, and ELP may be a potential therapeutic strategy to attenuate LAR mediated neuroinflammation after ICH."

Journal • Preclinical • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Immunology • Inflammation • RHOA

Repressing IRS1/2 by NT157 inhibits the malignant behaviors of ovarian cancer through inactivating PI3K/AKT/mTOR pathway and inducing autophagy. (PubMed, Kaohsiung J Med Sci) - "However, the autophagy inhibitor 3-MA partly reversed NT-157-mediated antitumor effects. In conclusion, this study disclosed that NT157 suppressed the malignant phenotypes of ovarian cancer cells by inducing autophagy and hampering the expression of IRS1/2 and PI3K/AKT/mTOR pathway."

Journal • Oncology • Ovarian Cancer • Solid Tumor • IRS1

NT157 exerts antineoplastic activity by targeting JNK and AXL signaling in lung cancer cells. (PubMed, Sci Rep) - "NT157 also presented potentiating effects on EGFR inhibitors in lung cancer cells. In conclusion, our preclinical findings highlight NT157 as a putative prototype of a multitarget drug that may contribute to the antineoplastic arsenal against lung cancer."

IO biomarker • Journal • Lung Cancer • Oncology • Solid Tumor • AXL • BBC3 • BCL2 • CCND1 • CDKN1A • CDKN1B • EGR1 • EIF4EBP1 • IRS1 • IRS2

IGF1R signalling is a guardian of self-tolerance restricting autoantibody production. (PubMed, Front Immunol) - "The mBSA-immunised mice were treated with synthetic inhibitor NT157 or short hairpin RNA to inhibit IGF1R signalling, and spleens were analysed by immunohistology and flow cytometry...In experimental model and in patient material, this study demonstrates that IGF1R plays an important role in preventing autoimmunity. The study raises awareness of that immune tolerance may be broken during therapeutic IGF1R targeting."

Journal • Immunology • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • CD14 • CXCR5 • IGF1R • IL10

NT157 inhibits cell proliferation and sensitizes glioma cells to TRAIL-induced apoptosis by up-regulating DR5 expression. (PubMed, Biomed Pharmacother) - "Importantly, combined administration of NT157 and TRAIL in vivo effectively inhibited glioma xenograft growth of nude mice by inhibiting cell proliferation and angiogenesis, and inducing DNA damage and apoptosis. Taken together, our findings validated the rational design that combined strategy of NT157 and TRAIL to trigger DNA damage and apoptosis by up-regulating DR5 could be a high efficient way to combat human glioma."

Journal • Brain Cancer • Glioma • Oncology • Solid Tumor • CASP3 • CDKN1A • TNFRSF10B

Effects of GABA receptor positive allosteric modulator BHF177 and IRS-1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway. (PubMed, Cell Biol Int) - "Next, we treated primary cultured rat hippocampal neurons with BHF177 and the IRS-1 selective inhibitor NT157. BHF177 inhibited hippocampal apoptosis in rat hippocampal neurons by regulating the IRS-1/PI3K/Akt axis through crosstalk between GABA and insulin-like growth factor-1 receptors. Collectively, our findings indicate that the BHF177 inhibited neuron apoptosis, thus protecting against RE through the IRS-1/PI3K/Akt axis, which may present a new therapeutic channel for RE."

IO biomarker • Journal • Preclinical • CNS Disorders • Epilepsy • Immunology • Inflammation • Oncology • BCL2 • CASP3 • ICAM1 • IRS1 • TNFA • VCAM1

Differential cytotoxic activity of pharmacological inhibitors of IGF1R-related pathways in JAK2 driven cells. (PubMed, Toxicol In Vitro) - "These inhibitors (NT157, OSI-906, and NVP-AEW54) present antineoplastic activity with similar efficacy in Ba/F3 JAK2 cells, with NT157 showing the greatest potency. Downregulation of JAK2/STAT signaling was an advantageous off-target effect of all three inhibitors. These preclinical studies reinforce the potential of the IGF1R-related pathway as a therapeutic target in MPN."

Journal • Myeloproliferative Neoplasm • Oncology • IGF1 • JAK2

IGF1R-IRS1/2 Pharmacological Inhibitors Act By Distinct Cellular and Molecular Mechanisms and Reveals Vulnerabilities for Treatment of Acute Myeloid Leukemia (ASH 2021) - "Considering a ≥ 2-fold change difference in both directions, linsitinib treatment downregulated 6 and 18 and upregulated 13 and 116 proteins in MOLM-13 and MV4-11 cells, respectively. Likewise, NT157 downregulated 12 and 126 and upregulated 204 and 297 proteins. When compared directly, linsitinib reduced expression of 11 and 35 and increased expression of 110 and 70 proteins in MOLM-13 and MV4-11 cells, respectively."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IGF1 • IGF1R • IRS1 • IRS2

NT157 Inhibits HCC Migration via Downregulating the STAT3/Jab1 Signaling Pathway. (PubMed, Technol Cancer Res Treat) - "Finally, high mRNA expression levels of signal transducer and activator of transcription-3 and c-Jun activation domain-binding protein-1 in hepatocellular carcinoma were associated with significantly low survival rates. NT157 inhibits hepatocellular carcinoma migration and metastasis by downregulating the signal transducer and activator of transcription-3/c-Jun activation domain-binding protein-1 signaling pathway and targeting it may serve as a novel therapeutic strategy for the clinical management of hepatocellular carcinoma in the future."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • JUN

[VIRTUAL] IGF1R DEPENDENT CELL INTERACTION AND REGULATION OF AUTOANTIBODY PRODUCTION IN RHEUMATOID ARTHRITIS (EULAR 2021) - "The mice were treated with a synthetic IGF1R inhibitor NT157 or with short hairpin RNA targeting IGF1R (shIGF1R) from the day prior to immunisation... We show that IGF1R signalling is important for immune cell communication after antigen challenge. IGF1R controls ICOSL dependent trafficking of B cells through the MZ and facilitates interaction with T cells. Retention of B cells in the MZ tips the balance from T cell to macrophage-dependent processes, which permits the formation of autoantibody producing B cells."

Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CD19 • CD21 • CD4 • CXCR5 • FCER2 • FOXO1 • IGF1R

NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia. (PubMed, Invest New Drugs) - "In human K562 cells and in murine Ba/F3 cells, engineered to express either wild-type BCR-ABL1 or the imatinib-resistant BCR-ABL1 mutant, NT157 inhibited BCR-ABL1, IGF1R, IRS1/2, PI3K/AKT/mTOR, and STAT3/5 signaling, increased CDKN1A, FOS and JUN tumor suppressor gene expression, and reduced MYC and BCL2 oncogenes. Exposure of primary CML cells harboring BCR-ABL1 to NT157 resulted in increased apoptosis, reduced cell proliferation and decreased phospho-CRKL levels. In conclusion, NT157 has antineoplastic effects on BCR-ABL1 leukemogenesis, independent of T315I mutational status."

IO biomarker • Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

[VIRTUAL] PHARMACOLOGICAL INHIBITORS OF IGF1R-IRS1 / 2 ACT BY DIFFERENT MECHANISMS AND REVEAL VULNERABILITIES FOR THE TREATMENT OF AML (HEMO 2020) - "The components of IGF1R-IRS1 / 2 were enriched with transcriptomic programs related to the maintenance of CTH and CTL. IRS2 was necessary for the viability and growth of AML cells. Proteomic data shed light on new and non-explicit mechanisms related to IGF1R-IRS1 / 2 inhibitors, while linsitinib modulates molecular processes related to RNA biology, NT157 profoundly affects cellular energy metabolism."

Acute Myelogenous Leukemia • Oncology • IGF1R • IRS2

FGFR1 overexpression renders breast cancer cells resistant to metformin through activation of IRS1/ERK signaling. (PubMed, Biochim Biophys Acta Mol Cell Res) - "Targeting IRS with IRS1 KO or IRS inhibitor NT157 significantly sensitized FGFR1 overexpressing cells to metformin. Moreover, we demonstrated that IRS1 functions as a critical mediator of the crosstalk between FGFR1 and IGF1R pathways, which involves a feedback loop between IRS1 and MAPK/ERK. Our study highlights the significance of FGFR1 status and IRS1 activation in metformin-resistance, which will facilitate the development of strategies targeting FGFR overexpression-associated metformin resistance."

Journal • Breast Cancer • Oncology • Solid Tumor • FGFR • FGFR1 • IGF1R