PTC-209 / PTC Therap - LARVOL DELTA

Targeting Dysregulated Epigenetic Modifiers with Kidney-Targeted Nanotherapeutics for PKD (KIDNEY WEEK 2025) - "Currently, tolvaptan, is the only FDA-approved therapy...To improve kidney-specific delivery, we encapsulated the small molecule inhibitors AZD-5153 (Brd4 inhibitor) and PTC-209 (BMi1 inhibitor) into kidney-targeting micelles (KMs) and evaluated their efficacy in human and murine ADPKD models...Conclusion We identified the epigenome as a therapeutic target for ADPKD and evaluated the efficacy of inhibiting Brd4 and BMi1 in ADPKD. We observed improved response upon loading inhibitors of the dysregulated epigenetic regulators into kidney-targeting nanoparticles and present a novel nanomedicine-based combinatorial therapeutic approach for ADPKD."

Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • BMI1 • BRD4 • PKD1 • PRKD1

Novel drug research and therapeutic strategies targeting tumor metastasis and cancer stem cells. (PubMed, Front Pharmacol) - "PTC 209 utilizes the high affinity of modified hyaluronic acid nanoparticles for colorectal cancer to reverse CSC stemness in colorectal cancer...These strategies emphasize specificity, nanodelivery, and combination therapies to reduce toxicity and resistance, highlighting precision oncology potential. Clinical validation remains critical for translation."

Journal • Review • Colorectal Cancer • Liver Cancer • Oncology • Solid Tumor • PSMD14

Reduced level of BMI1 inhibits trophoblast proliferation and migration via the epigenetic enhancement of CSTA and TGFB2 in spontaneous abortion. (PubMed, Placenta) - "The regulation of trophoblast function by BMI1, including the production of ROS in the cytoplasm and the epigenetic modifications of CSTA and TGFB2 in nuclei, could facilitate the identification of mechanisms underlying SA."

Journal • BMI1 • TGFB2

Bmi1 regulates neural differentiation of mesenchymal stem cells through the Wnt3a‑RhoA signaling pathway to repair ischemic brain injury in rats. (PubMed, Int J Mol Med) - "In the present study, in vitro experiments were performed using the Wnt signaling agonist Wnt3a and the B lymphoma Mo‑MLV insertion region 1 homolog (Bmi1) small molecule inhibitor PTC209 to treat MSCs, and the roles and regulatory mechanisms of the Bmi1 and Wnt3a‑RhoA signaling pathways on the neural differentiation of MSCs were explored by MTT assay, immunofluorescence analysis and western blotting...The findings suggested that Bmi1 modulates the neural differentiation of MSCs through its regulatory effects on Wnt3a and RhoA expression, thereby influencing the reparative potential of MSCs in ischemic brain tissue. These findings highlight the therapeutic relevance of targeting Wnt3a‑RhoA activation and Bmi1 inhibition in MSC‑based interventions for IBI."

Journal • Preclinical • CNS Disorders • Hematological Malignancies • Lymphoma • Oncology • Transplantation • Vascular Neurology • BMI1 • RHOA • WNT3A

Pharmacologic inhibition of BMI1 exerts antitumor effects against MYCN-amplified neuroblastoma, with activation of the p53 pathway. (PubMed, Sci Rep) - "In our present study, the BMI1 inhibitors PTC-028 and PTC-209 exhibited selective antitumor activity against MYCN-amplified neuroblastoma. Significantly, PTC-028 also exhibited antitumor efficacy in a mouse xenograft model of human neuroblastoma. These results suggest that BMI1 inhibitors, particularly PTC-028, are promising therapeutic agents for the management of aggressive MYCN-amplified neuroblastomas."

Journal • Neuroblastoma • Oncology • Solid Tumor • BCL2 • BMI1 • MCL1 • MYCN

BMI1 facilitates Wnt signaling by epigenetic silencing of Axin2 to promote cell proliferation and migration in Hirschsprung's disease. (PubMed, Integr Biol (Camb)) - "Pharmacological inhibition of BMI1 using PTC-209 significantly attenuated cell proliferation, migration, and cell cycle progression in both SH-SY5Y neuroblastoma cells and primary enteric neural crest cells (ENCCs), whereas BMI1 overexpression produced the opposite effects...Molecular level probing revealed that BMI1 binds to the promoter region of Axin2, an inhibitor of the Wnt signaling pathway, and inhibited Axin2 transcription by increasing H2AK119ub and decreasing H3K4me3 in the Axin2 promoter, thereby hindering Wnt signaling. This study revealed that the BMI1/Axin2/Wnt axis may play an important role in the pathogenesis of HSCR."

Journal • Gastrointestinal Disorder • Neuroblastoma • Oncology • Rare Diseases • Solid Tumor • AXIN2 • BMI1 • EDNRB

The BMI1-Angiopoietin-2 axis as an independent prognostic factor in colorectal cancer. (PubMed, Exp Cell Res) - "BMI1 promotes angiogenesis in CRC by upregulating ANGPT2 expression. High BMI1 and ANGPT2 levels served as independent prognostic factors for tumor progression, highlighting their potential as therapeutic targets for CRC management."

Biomarker • Journal • Colorectal Cancer • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Solid Tumor • ANGPT2 • BMI1

CD44-targeted virus-mimicking nanomedicine eliminates cancer stem cells and mitigates chemoresistance in head and neck squamous cell carcinoma. (PubMed, Mater Today Bio) - "Using a series of preclinical models in murine systems, we confirmed that PTC209@VNP-HA eliminated BMI1+ CSCs, and greatly inhibited the proliferation and metastasis of HNSCC when combined with cisplatin. This study investigated PTC209@VNP-HA as a novel and potentially transformative HNSCC treatment option that eliminates CSCs, prevents metastasis, and overcomes cisplatin resistance."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BMI1

Targeting Dysregulated Epigenetic Modifiers With Kidney-Targeted Nanotherapeutics for Polycystic Kidney Disease. (PubMed, J Biomed Mater Res A) - "The one small molecule drug available to patients, tolvaptan, is associated with off-target side effects and high discontinuation rates, necessitating the development of new therapeutic strategies...We found Brd4 and BMi1 are upregulated and observed that their inhibition using small molecule drugs, AZD-5153 and PTC-209, significantly slowed the proliferation of ADPKD patient cells...These findings were also consistent in murine in vitro models using Pkd1 null renal proximal tubule cells. In summary, we demonstrate Brd4 and BMi1 as novel targets in ADPKD and targeting the epigenome using kidney nanomedicine as a novel therapeutic strategy in ADPKD."

Journal • Autosomal Dominant Polycystic Kidney Disease • Chronic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • BMI1 • BRD4 • PKD1 • PRKD1

A Hybrid Manganese Nanoparticle Simultaneously Eliminates Cancer Stem Cells and Activates STING Pathway to Potentiate Cancer Immunotherapy. (PubMed, ACS Nano) - "PTC209/MnO2@BSA (bovine serum albumin) nanoparticles (PMB NPs) synthesized via a facile and green process are reported, wherein the released manganese (Mn) ions under acidic tumor microenvironment significantly enhance cGAS-STING signals and facilitate the dendritic cells maturation to unleash the T-cell-mediated immune response...Both in vitro and in vivo experiments elucidate that PMB NPs function as designed, exerting powerful immunotherapeutic and chemotherapeutic impacts to impede HNSCC growth and metastasis as well as bolster anti-PD-1-based ICB. Collectively, our findings provide a promising therapeutic strategy against HNSCC by combinational CSCs elimination and STING activation via metalloimmunotherapy."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BMI1

Discovery and optimization of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel phosphodiesterase 4 inhibitors. (PubMed, Mol Divers) - "In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC50 of 4.78 ± 0.08 μM)...L19, the most potent inhibitor, exhibited good inhibitory activity (IC50 of 0.48 ± 0.02 μM) and remarkable metabolic stability in rat liver microsomes. Our study presents an example of discovery novel PDE4 inhibitors, which would be helpful for design and optimization of novel inhibitors in future."

Journal

Optimization of Epigenetic Modifier Drug Combination for Synergistic Effect against Glioblastoma Multiform Cancer Cell Lines. (PubMed, Cancer Invest) - "Cell lines were treated with SAHA, 5-Azacytidine, GSK-126, and PTC-209 individually and then RSM was used to find most effective combinations. Results showed that optimized combinations significantly reduce cell survival and induce cell cycle arrest and apoptosis in both cell lines. Expression of cyclin B1 and cyclin D1 were decreased while caspase3 increased expression."

Journal • Preclinical • Brain Cancer • CNS Tumor • Gene Therapies • Glioblastoma • Oncology • Solid Tumor • CASP3 • CCNB1 • CCND1

Peptidase inhibitor 16 promotes inflammatory arthritis by suppressing Foxp3 expression via regulating K48-linked ubiquitin degradation Bmi-1 in regulatory T cells. (PubMed, Clin Immunol) - "Furthermore, Bmi-1 specific inhibitor PTC209 could restore Foxp3 expression and alleviate arthritis progression in PI16 mice, accompanied by increased recruitment of active histone mark in the promoter of Tregs. Our results suggest that PI16-Bmi-1 axis plays an important role in RA and other autoimmune diseases by suppressing Foxp3 expression in Tregs via Bmi-1-mediated histone modification."

Journal • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • Targeted Protein Degradation • BMI1 • FOXP3 • PI16

BMI1 Silencing Liposomes Suppress Postradiotherapy Cancer Stemness against Radioresistant Hepatocellular Carcinoma. (PubMed, ACS Nano) - "The suppression of the radioresistant performance of LP(PTC-209) has been proved on radiosensitive and radioresistant Hepa1-6 CSC tumor models, respectively. Our study clarified the relationship between radiotherapy and cancer stemness and provided insights to achieve complete suppression of radioresistant HCC tumor by inhibiting cancer stemness."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • BMI1

Epigenetic Dysregulation of CML (SOHO 2023) - "Consistent with our model, we found the combination of PRC1 (PTC-209) and DNA methylation (decitabine) inhibitors was particularly effective against BC progenitors, including extinguishing their stemness function. This model highlights the contribution of epigenetic dysregulation to drug resistance transcriptomes, while also incorporating the contribution of genetic mutations. Our results also suggest that epigenetic therapy, given early enough in the course of disease progression, may also prevent the emergence of drug-resistant clones and fullblown BC."

Oncology • ABL1 • CD34 • RUNX1

Modeling human brain rhabdoid tumor by inactivating tumor suppressor genes in induced pluripotent stem cells. (PubMed, Bioact Mater) - "Ribociclib, PTC-209, and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells. This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing."

Journal • Brain Cancer • Embryonal Tumor • Oncology • Rhabdoid Tumor • Sarcoma • Solid Tumor • CTNNB1 • NANOG • NPM1 • POU5F1 • SMARCB1 • SPP1 • TP53

Core-Shell Cisplatin/SiO2 Nanocapsules Combined with PTC-209 Overcome Chemotherapy-Acquired and Intrinsic Resistance in Hepatocellular Carcinoma. (PubMed, Acta Biomater) - "Additionally, HCC stem cell inhibitors can reverse intrinsic resistance by inhibiting HCC stem cells. Therefore, this study contributes to the application of DDS in combating drug resistance in HCC and enhances its potential for clinical implementation."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • BMI1

The proto-oncogene Bmi1 is a novel regulator of the activated hepatic stellate phenotype (EASL-ILC 2023) - "The small molecule inhibitor PTC-209 was used to inhibit BMI1 in ex vivo culture activated HSCs... In this study, we provide proof-of-concept data demonstrating ex vivo inhibition of BMI1 abrogates the profibrotic phenotype of activated HSCs. Moreover, we have identified a potentially new target linked to epigenetic mechanisms in the ongoing search for anti-fibrotic therapies in chronic liver disease."

Biliary Cancer • Cholangiocarcinoma • Fibrosis • Gastrointestinal Cancer • Hematological Malignancies • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Leukemia • Liver Cirrhosis • Oncology • Solid Tumor • Targeted Protein Degradation • BMI1 • COL1A1 • PCNA • PDGFRB • SOX9 • YAP1 • YBX1

Alpha-tocopherol enhances spermatogonial stem cell proliferation and restores mouse spermatogenesis by up-regulating BMI1. (PubMed, Front Nutr) - "Furthermore, α-tocopherol restored sperm count (Ctrl vs. PTC-209, p = 0.0034; Ctrl vs. PTC-209 + α-tocopherol, p = 0.7293) and normalized sperm malformation such as broken heads, irregular heads, lost and curled tails in vivo, as demonstrated by its antagonism with the BMI1 inhibitor PTC-209. Analysis demonstrated that α-tocopherol is a potent in vitro and in vivo modulator of BMI1, a transcription factor that plays an important role in in SSC proliferation and spermatogenesis. Our findings identify a new target and strategy for treating male infertility that deserves further pre-clinical investigation."

Journal • Preclinical • Hematological Malignancies • Infertility • Lymphoma • Oncology • Sexual Disorders • BMI1

BMI1 Regulates Proliferation of Human Late-Stage Erythroid Progenitors (ASH 2022) - "In support of this hypothesis, treatment of human CD34+ cell erythroid cultures with the BMI1 inhibitors, PTC209 or PTC028, reduced late-stage (EP3 and EP4), but not immature (EP1 or EP2), erythroid progenitor numbers. Interestingly, SRE proliferation was significantly, but not completely, rescued by the addition of exogenous lipids, highlighting the importance of cholesterol metabolism in human SRE proliferation. These findings, taken together, support the hypothesis that BMI1 regulates erythroid self-renewal through several mechanisms including the cell cycle and cholesterol biosynthesis."

BMI1 • CD34

Glucose and Cell Context-Dependent Impact of BMI-1 Inhibitor PTC-209 on AKT Pathway in Endometrial Cancer Cells. (PubMed, Cancers (Basel)) - "Our results indicate that the relationship between BMI-1 and phosphatases involved in AKT regulation depends on the glucose concentration and insulin stimulation."

Journal • Diabetes • Endometrial Cancer • Hypoglycemia • Oncology • Solid Tumor • CDH1 • PHLPP1 • PTEN • SNAI2

BMI-1 promotes breast cancer proliferation and metastasis through different mechanisms in different subtypes. (PubMed, Cancer Sci) - "More importantly, we discovered that knockdown of CDKN2D/BRCA1 could promote cell proliferation and migration after repression by PTC-209. Our results reveal that BMI-1 transcriptionally suppressed BRCA1 in TNBC cell lines, whereas in luminal A cell lines, CDKN2D was the target gene. This provides a reference for the precise treatment of different types of breast cancer in clinical practice."

Journal • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Triple Negative Breast Cancer • BMI1 • BRCA1

The Systematic Analyses of RING Finger Gene Signature for Predicting the Prognosis of Patients with Hepatocellular Carcinoma. (PubMed, J Oncol) - "Moreover, the inhibitor of BMI1, PTC-209, displayed an excellent anti-HCC effect in vitro. Enrichment analysis of BMI1 downstream targets showed that BMI1 might be involved in tumor immunotherapy. Together, our overall analyses revealed that the 11-RNFs prognostic signature might provide us latent chances for evaluating HCC prognosis and developing novel HCC therapy."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • BMI1 • TRIM38

Expression and therapeutic targeting of BMI1 in canine gliomas. (PubMed, Vet Comp Oncol) - "The BMI1 inhibitor, PTC-209, suppressed BMI1 expression in established canine glioma cell lines and resulted in antiproliferative activity when used alone and in combination with chemotherapeutic agents...PTC-209 targeting of BMI1 activated the RB pathway through downregulation of total and phosphorylated RB, independent of INK4A/ARF signaling, likely through BMI1-inhibition mediated upregulation of p21. These data support the rationale for targeting of BMI1 signaling and the use of canine glioma as a translational therapeutic model for human disease."

Journal • Brain Cancer • Glioma • Oncology • Solid Tumor • BMI1 • CDKN1A • CDKN2A

The ErbB3 Receptor Restricts Bmi1 to Regulate Paneth Cells. (PubMed, FASEB J) - "Our data demonstrate that ErbB3 regulates Bmi1 expression through PI3K/Akt and MAPK signaling in both human and mouse intestinal cells. Furthermore, BMI1 activity promotes LYZ1 expression. Together, these results support our hypothesis that ErbB3 regulates secretory cell differentiation through BMI1 in the intestinal epithelium."

Journal • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • AKT1 • BMI1 • ERBB3