picropodophyllin (AXL1717) / Axelar - LARVOL DELTA

Ferric ion-crosslinked hydrogel patch loaded with IGF-1R inhibitor for the treatment of heterotopic ossification through microenvironment multifaceted regulation. (PubMed, Biomaterials) - "Herein, we fabricated a targeted drug delivery system by loading picropodophyllin (PPP), an IGF-1 receptor (IGF-1R) inhibitor, into mesoporous silica nanoparticles (MSNs)...Mechanistically, these regulatory effects were mediated through the suppression of the PI3K-Akt signaling pathway and the activation of mitophagy. In conclusion, the PCL@HA-ADH@PA/Fe@MSNP patch developed based on the "microenvironment multifaceted regulation" strategy enables synergistic HO prevention, providing a promising and translatable therapeutic approach for tendon repair."

Journal • Inflammation • Pain • IGF1

Dual targeting of IGF-1R and K-RAS with natural phytochemicals for lung cancer therapy: an in-silico study. (PubMed, J Genet Eng Biotechnol) - "According to the results, 17Beta-Hydroxywithanolide K and Ginkgolide A demonstrated strong binding affinity to IGF-1R (-9.4 Kcal/mol) and KRAS (-6.9 Kcal/mol), respectively, compared to the synthetic inhibitors Picropodophyllin (-7.7 Kcal/mol) and Sotorasib (-5.9 Kcal/mol). Overall, 17Beta-Hydroxywithanolide K and Ginkgolide A have potential as natural therapeutic agents for the treatment of lung cancer. However, additional in vitro and in vivo experiments are needed to validate these computational results."

Journal • Lung Cancer • Oncology • Solid Tumor • KRAS

Isoliensinine Ameliorates Postoperative Neurocognitive Disorder in Aged Mice by Restoring Hippocampal IGF-1 Receptor Signaling and Suppressing Oxidative Stress and Neuroinflammation. (PubMed, Eur J Pharmacol) - "These neuroprotective effects were causally linked to IGF1R activation, as co-administration of the selective IGF1R inhibitor picropodophyllin (PPP) completely abolished ISL's therapeutic benefits...In conclusion, our findings demonstrate that ISL ameliorates PND by reactivating the neuronal IGF-1/IGF1R signaling pathway, which in turn suppresses downstream oxidative stress and microglial-driven neuroinflammation. This highlights ISL as a promising therapeutic candidate for the prevention and treatment of PND."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Developmental Disorders • Inflammation • Psychiatry • IGF1 • IGF1R

An Integrated Approach Combining Surface Plasmon Resonance Screening with Proteomics Enables Discovery of Natural Molecular Glue Degraders. (PubMed, JACS Au) - "Subsequent investigations demonstrated that triptolide facilitates VHL-mediated degradation of IMP3, whereas picropodophyllin promotes Keap1-mediated degradation of DDX52 and LDHB. These degradation events were confirmed to depend on the respective E3 and ubiquitin-proteasome system, underscoring the capacity of these compounds to induce ternary complex formation. In conclusion, the establishment of SPR-DI provides a promising tool for the discovery of MGDs and their corresponding POIs, offering instructive insights to advance future MGD screening methodologies."

Journal • Targeted Protein Degradation • KEAP1 • LDHB

Unveiling bioactive compounds in kola nut seeds: GC-MS identification and computational analysis for anticancer potential. (PubMed, Front Nutr) - "From these, 15 bioactive compounds, including scopolin, picropodophyllin, catechin, yohimbine, squalene, campesterin, epicatechin, stigmasterol, p-coumaric acid, quinoline, methyl linoleate, methyl oleate, DTB-spdione, theobromine, and caffeine, were shortlisted for in silico docking studies...Based on enhanced fractionations, our study provides an expanded chemical profile of kola nut seeds and suggests that selected phytochemicals may serve as promising candidates for anticancer drug development. Further experimental validation is warranted to translate these insights into therapeutic applications."

Journal • Oncology • PIK3CA

Downregulation of Insulin-Like Growth Factor I (IGF-1) Signaling Induces Cell Senescence in Vascular Smooth Muscle Cells: Implications for Atherosclerotic Plaque Progression (AHA 2025) - "Cell senescence is an irreversible cell proliferation arrest associated with the progression of atherosclerosis, however specific mechanisms linking senescence with atherogenesis remain to be identified.Hypothesis: We hypothesized that IGF1 receptor (IGF1R) downregulation would induce SMC senescence in vitro and that activation of IGF1R signaling would suppress SMC senescence in the atherosclerotic plaque. Bleomycin (10ug/ml, 5d)-treated aortic SMC were used as in vitro senescence model...SMC treatment with 3uM picropodophyllin (IGF1R inhibitor) or with 100nM ganitumab (IGF1R antibody) decreased IGF-1-induced signaling, arrested SMC proliferation and upregulated senescence markers (βGal activity and γ-H2AX expression) showing that specific inhibition of IGF-1 signaling induces cell senescence... IGF1R downregulation induced SMC senescence in vitro and activation of IGF1R signaling downregulated senescence markers, and decreased levels of SMC-like senescent cells in the..."

Atherosclerosis • APOE • CDKN1A • H2AX • IGF1 • IGF1R

Reciprocal regulation between B lymphoma Mo-MLV insertion region 1 homolog and type I insulin-like growth factor receptor in pemetrexed-resistant lung cancer cells. (PubMed, Tzu Chi Med J) - "IGF-1R inhibition was performed by picropodophyllin (PPP), an IGF-1R inhibitor, or by shRNA-mediated RNA silencing. Further investigation showed that BMI1 knockdown in A400 cells resulted in decreased IGF-1R phosphorylation, whereas BMI1 overexpression in A549 cells resulted in increased IGF-1R phosphorylation, indicating an interaction between these two proteins. A novel reciprocal regulatory relationship between IGF-1R and BMI1 has been identified in lung cancer cells, suggesting potential therapeutic strategies to combat pemetrexed resistance in lung cancer patients."

Journal • Genetic Disorders • Hematological Malignancies • Immunology • Lung Cancer • Lymphoma • Obesity • Oncology • Primary Immunodeficiency • Solid Tumor • BMI1

IGF1/IGF1R signaling promotes the expansion of liver CSCs and serves as a potential therapeutic target in HCC. (PubMed, Discov Oncol) - "Furthermore, IGF1R inhibition by inhibitor effectively eliminated liver CSCs and inhibited the growth of tumors and metastasis in vivo. These findings uncover the important role of IGF1/IGF1R signaling in liver CSCs, and also provide a promising diagnostic marker as well as therapeutic intervention for HCC."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CD133 • IGF1 • IGF1R • THY1

Picropodophyllin induces ferroptosis via blockage of AKT/NRF2/SLC7A11 and AKT/NRF2/SLC40A1 axes in hepatocellular carcinoma as a natural IGF1R inhibitor. (PubMed, Phytomedicine) - "The natural IGF1R inhibitor PPP induced ferroptosis through blockage of PI3K/AKT/NRF2 signaling pathway and subsequent inhibition of downstream gene expression of SLC7A11 and SLC40A1 in hepatocellular carcinoma. Consequently, our findings provide a novel action and mechanism of PPP, as well as offer innovative and promising ferroptosis-inducing agents for the clinical treatment of HCC."

Journal • Hematological Disorders • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • GPX4 • SLC40A1 • SLC7A11

IGF-1 promotes trophectoderm cell proliferation of porcine embryos by activating the Wnt/β-catenin pathway. (PubMed, Cell Commun Signal) - "Our findings provide new insights into the interaction between IGF-1 and the Wnt/β-catenin signaling pathway during embryogenesis and highlight the potential of IGF-1 to improve reproductive outcomes by enhancing TE formation and quality."

Journal • Preclinical • IGF1

HBx/WDR5 enhances IGF-1 transcription in hepatocellular carcinoma cells and promotes recruitment, infiltration, and activity of Treg cells. (PubMed, Immunol Res) - "In the cell co-culture system, HBx/IGF-1 signaling in HCC cells promoted Treg cells expansion, IL-10 secretion, and infiltration, which was blocked by the IGF-1R inhibitor picropodophyllin...IGF-1/IGF-1R signaling plays an important role in the communication between HCC cells and Treg cells. Targeting WDR or IGF-1/IGF-1R would be beneficial for the treatment of HCC."

Journal • Hepatitis B • Hepatocellular Cancer • Hepatology • Infectious Disease • Oncology • Solid Tumor • IGF1 • IL10 • WDR5

Picropodophyllin, an IGF‑1 receptor inhibitor, enhances oxaliplatin efficacy in chemoresistant colorectal cancer HCT116 cells by reducing metastatic potential. (PubMed, Oncol Lett) - "Immunofluorescence staining revealed that this combination also significantly increased E-cadherin expression, by 1.37- and 1.63-fold, respectively (P<0.05), indicating the role of PPP in enhancing epithelial characteristics and reducing EMT-related drug resistance. These findings highlight the potential for combining PPP with OX to enhance the cytotoxic and anti-metastatic effects of OX in chemo-resistant CRC cells, thus offering a promising strategy for overcoming drug resistance and improving patient outcomes in CRC treatment."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CDH1 • IGF1 • VIM

IGF1R/ARRB1 Mediated Regulation of ERK and cAMP Pathways in Response to Aβ Unfolds Novel Therapeutic Avenue in Alzheimer's Disease. (PubMed, Mol Neurobiol) - "Here, we focused on the ARRB1 and IGF1R interaction and showed that picropodophyllin (PPP), an IGF1R-specific inhibitor, blocks this interaction and alters the ERK and cAMP status under disease conditions. Cell viability studies further revealed that the PPP substantially improved cell viability in the presence of Aβ. This highlights the role of the PPP in regulating these cascades and opens the arena for further therapeutic development for AD."

Journal • Alzheimer's Disease • CNS Disorders • ARRB1 • IGF1R • IR

Traditional pediatric massage exerted an antidepressant effect and activated IGF-1/Nrf2 pathway in CUMS-exposed adolescent rats. (PubMed, J Neuroimmunol) - "With the treatment of picropodophyllin, the inhibitor of IGF-1 receptor, the antidepressant effect of TPM was blocked, along with inhibited IGF-1/Nrf2 pathway which were closely related with anti-inflammatory and anti-ferroptosis actions. The results suggest that TPM enhanced the resilience of adolescent rats to CUMS and exerted an antidepressant effect partially via activating IGF-1/Nrf2 pathway."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Pediatrics • Psychiatry • IGF1

Interaction with IGF1 overrides ANXA2-mediated anti-inflammatory functions of IGFBP5 in vivo. (PubMed, Front Immunol) - "An IGF1R inhibitor picropodophyllin antagonized functions of IGF1/IGF1R too, but didn't reinforce the effects of IGFBP5. IGFBP5 eases inflammation by interacting with ANXA2, an activator of NF-κB; as an antagonist of IGF1/IGF1R, IGFBP5 may disrupt immune homeostasis in vivo, due to impairment of the latter's anti-inflammatory functions; excessive IGFBP from adipocytes would be a pathogenic factor in certain diseases."

Journal • Preclinical • Acute Lung Injury • Immunology • Inflammation • Inflammatory Arthritis • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • ANXA2 • IGF1 • IGFBP5 • IL1B • IL6

Establishing a new human lung squamous cell carcinoma cell line, OMUL-1, expressing insulin-like growth factor 1 receptor and programmed cell death ligand 1. (PubMed, Thorac Cancer) - "We developed a novel new squamous cell lung carcinoma cell line, OMUL-1, that expresses IGF1R and PD-L1."

IO biomarker • Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • EGFR • ERBB3 • ERBB4 • FGFR1 • FGFR2 • FGFR3 • FGFR4 • FLT4 • HER-2 • IGF1R • MET • NKX2-1 • PDGFRA • PDGFRB • PD-L1 • TP63

oHSV and radiation therapies sensitize glioblastoma to IGF1R-targeted therapy and synergize in triple combination therapy (SNO 2024) - "While IGF1R targeting therapies (e.g., OSI-966, Picropodophyllin (PPP)) have displayed limited efficacy in clinical trials, they significantly increased oHSV-induced cytotoxicity in all tested primary GBM cells compared to either agent alone in vitro and in vivo, resulting in a dose-dependent increase in PARP and caspase 3 activity by western blot and immunohistochemistry...Triple combination therapy with oHSV, IGF1R inhibition, and RTx significantly increased tumor cell killing in vitro and improved survival of orthotopic GBM tumor-bearing mice. Collectively, our study provides preclinical evidence of enhanced therapeutic efficacy of oHSVs and RTx in combination with IGF1R blockade, supporting future use of IGF1R inhibitors in combination with the standard of care and FDA-approved oHSV therapies in patients with GBM."

Combination therapy • IO biomarker • Brain Cancer • CNS Tumor • Glioblastoma • Herpes Simplex • Infectious Disease • Oncology • Solid Tumor • CASP3 • IDH1 • IGF2

TLR9-dependent autophagy and IGF1R inhibition affect apoptosis and stem cell phenotype in the HT29 cell line (DGHO 2024) - " HT29 tumor cells were treated with cell-free DNA (Kg), IGF1R inhibitor picropodophyllin (P), autophagy inhibitor chloroquine (C), and in a triple combination (gPC), in addition to control (K) cells. Co-inhibition of TLR9-mediated autophagy and IGF1R signaling by increasing the Bax/Bcl2 ratio substantially enhances the apoptosis sensitivity of HT29 cells (high Bax/Bcl-2 ratio, increased caspase 3, 8, and 9 activity). At the same time, MAPK/NF-kB activation may contribute to the survival of CD133+ stem cell phenotype HT29 cells."

IO biomarker • Preclinical • Oncology • AKT1 • BAX • BCL2 • CASP3 • CASP8 • CASP9 • CD133 • PI3K • TLR9

Tumor-derived cell-free DNA in combination with IGF1R inhibition results in a strong antiproliferative effect but increases the survival of stem-like HT29 cells (DGHO 2024) - " HT29 tumor cells were treated with free-DNA (Kg), IGF1R inhibitor picropodophyllin (P), and a combination of free-DNA and IGF1R inhibitor (gP), in addition to control (K) cells... Active mTOR in gP-treated HT29 cells suggests autophagy inhibition. Increased CD133 expression suppresses autophagy by limiting ULK1 activation, thereby promoting the maintenance of an undifferentiated, CD133+ stem cell-like phenotype via activation of NF-kB. The gP combined treatment has a potent antiproliferative effect but also promotes the formation of cancer stem cells, which may play a role in disease recurrence."

Cell-free DNA • Combination therapy • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ATG16L1 • BECN1 • CD133 • TLR9

Hypoxia-induced TIMAP Upregulation in Endothelial Cells and TIMAP-dependent Tumour Angiogenesis. (PubMed, Am J Physiol Cell Physiol) - "Conversely, hypoxia and the prolyl hydroxylase inhibitor Roxadustat raised TIMAP mRNA and protein levels by inhibiting the BMP9 pathway...Cultured breast cancer E0771 cells released mediators that raised TIMAP expression in endothelial cells, effects that were inhibited by the VEGF inhibitor Sunitinib in conjunction with the IGF-1 inhibitor Picropodophyllin. In the mouse E0771 breast cancer model in vivo, tumor growth and tumor angiogenesis were markedly attenuated in TIMAP deficient, compared to wild-type littermates. These findings indicate that TIMAP plays a critical pro-angiogenic function during tumor angiogenesis in vivo, likely through hypoxia-driven inhibition of the BMP9 pathway and through elaboration of angiogenic growth factors by tumor cells."

Journal • Breast Cancer • Oncology • Solid Tumor • IGF1 • TGFB1

Targeting IGF1/IGF1r signaling relieve pain and autophagic dysfunction in NTG-induced chronic migraine model of mice. (PubMed, J Headache Pain) - "Our findings demonstrate that in the chronic migraine (CM) model in mice, there is a significant increase in IGF1 expression in the TNC region. This upregulation of IGF1 leads to enhanced phosphorylation of IGF1 receptors on neurons. Targeting and inhibiting this signaling pathway may offer potential preventive strategies for mitigating the progression of chronic migraine."

Journal • Preclinical • CNS Disorders • Immunology • Migraine • Pain • FOS • IGF1

Neohesperidin alleviates the inhibitory effect of bisphenol A on the myogenic differentiation of umbilical cord mesenchymal stem cells via the IGF1R/AKT1/RHOA signaling pathway. (PubMed, Ecotoxicol Environ Saf) - "Western blot results showed that NEO could reverse the down-regulation of the pathway proteins induced by BPA, and counteract the effects of picropodophyllin (PPP) or MK-2206 dihydrochloride (MK-2206) in the myogenic differentiation of sheep UC-MSCs. Taken together, the mechanisms of NEO resistance to BPA involved the IGF1R/AKT1/RHOA signaling pathway. These findings provide a scientific basis for alleviating BPA toxicity, preventing and treating muscular dysplasia, and promoting muscle damage repair."

Journal • AKT1 • RHOA

Caffeic acid and diabetic neuropathy: Investigating protective effects and insulin-like growth factor 1 (IGF-1)-related antioxidative and anti-inflammatory mechanisms in mice. (PubMed, Heliyon) - "Additionally, to determine the specific contribution of IGF-1 signaling to the observed benefits, IGF1R inhibitor Picropodophyllin (PPP) was co-administered with caffeic acid...Our findings delineate the capability of caffeic acid to mitigate DN symptoms, particularly through reducing spinal oxidative stress and inflammation, and pinpoint the integral role of IGF-1 signaling in these protective mechanisms. The insights gleaned from this study not only position caffeic acid as a promising dietary adjunct for managing diabetic neuropathy but also highlight the therapeutic potential of targeting spinal IGF-1 signaling as part of a strategic treatment approach."

Journal • Preclinical • Diabetes • Diabetic Neuropathy • Inflammation • Metabolic Disorders • Pain • IGF1

Insulin-like Growth Factor Receptor Type-1 in Schwann Cells Regulates Pain in a mouse model of Metastatic Bone Cancer Pain (EACR 2024) - "Adeno-associated virus-based shRNA selective silencing of IGF-1R in Schwann cells or systemic administration of the IGF-1R inhibitor, picropodophyllin (PPP), attenuated pain-like behaviors...Activated TRPA1 releases macrophage-colony stimulating factor (M-CSF) that promotes endoneurial macrophage expansion and the ensuing reacConclusion In the present MBCP model, E0771 breast carcinoma cells growing in the femur metastasis release osteoclasts to liberate IGF-1. Schwann cell IGF-1R signaling promoted an endothelial nitric oxide synthase-mediated TRPA1 activation and release of ROS that, via M-CSF-dependent endoneurial macrophage expansion, sustained pain-like behaviors."

Metastases • Preclinical • Breast Cancer • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor • CSF1 • IGF1 • TRPA1

ANALYSIS OF SIGNALING PATHWAYS THAT CONTROL PROGENITOR EPITHELIAL CELL PROLIFERATION & DIFFERENTIATION USING HUMAN LUNG ORGANOIDS (WRMC 2024) - "Consistent with the latter findings, inhibition of IGF1R by picropodophyllin (PPP) reduced cell proliferation. In contrast to IGF1, blocking HGF signaling by capmatinib affected both cell proliferation and AT1 lineage gene expression as evidenced by robust increased expression of HOPX. The studies using the distal lung tips that contain pluripotent progenitor cells demonstrate that at least some of the functional findings regarding the role of IGF1 and HGF signaling pathways in niche-epithelial cell cross-communication may be conserved between mouse and human. Current studies are underway to elucidate the function of this cross-communication in more detail."

Bronchopulmonary Dysplasia • Pulmonary Disease • Respiratory Diseases • IGF1 • SOX2 • SOX9