BIBR1532 / Boehringer Ingelheim - LARVOL DELTA

Telomere Attrition-Induced Senescence in Human Pluripotent Stem Cell-Derived Astrocytes: Distinct Cellular and Functional Characteristics. (PubMed, J Cell Physiol) - "Treatment with the telomerase inhibitor BIBR1532 (BIBR) during differentiation induced hallmark features of senescence, including nuclear lamina abnormalities, enhanced senescence-associated β-galactosidase activity, increased replication arrest and DNA damage, altered reactive oxygen species homeostasis in mitochondria, accompanied by significant shortening of relative telomere length...Our results reinforce the notion that while telomere attrition is a major cellular senescence driver, its onset may not be attributed to a single stressor but rather to a complex interplay of cellular stress pathways. This study provides valuable insights into the mechanisms underlying astrocytic senescence and underscores the need for further research on the molecular basis of its occurrence and functional implications."

Journal

Combined Inhibition of telomerase and mitochondria synergistically promote apoptosis in AML cell lines. (PubMed, Med Oncol) - "This investigation assessed the impact of concurrently targeting telomerase with BIBR1532 and mitochondrial function with Tigecycline on inducing apoptosis in AML cell models. Also, TI/MI significantly changed Bax and Bcl-2 protein levels and reduced telomere length. In conclusion, the combined use of TI/MI induced anti-proliferative effects and induction of apoptosis by down-regulation of anti-apoptotic and up-regulation of pro-apoptotic genes and proteins levels and shortening of telomere length on AML cells."

IO biomarker • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BAX • BCL2 • BCL2L1

Gadd45B Deficiency Drives Radio-Resistance in BRAFV600E-Mutated Differentiated Thyroid Cancer by Disrupting Iodine Metabolic Genes. (PubMed, Cancers (Basel)) - "Gadd45B plays a pivotal role in regulating the differentiation status and RAI sensitivity of BRAFV600E-mutated thyroid cancer. These findings identify Gadd45B as a promising therapeutic target for restoring RAI responsiveness in RAIR-DTC patients."

Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma • GADD45B • MYC

Telomerase inhibitors - TMPyP4, BIBR 1532 and imetelstat - alter the adhesion potential of breast cancer MCF7 and MDA-MB-231 cells that leads to impaired ability to form spheroids. (PubMed, Cell Adh Migr) - "Molecular docking and molecular dynamic studies showed that both BIBR 1532 and TMPyP4 exhibited affinity toward the structure of a G-quadruplex of human telomeric RNA (TERRA2 G4s) and the catalytic subunit of telomerase, hTERT. We showed that the use of telomerase expression/activity inhibitors to reduce the adhesive capacity and metastatic potential of breast cancer cells may play a significant role in anticancer strategy."

Journal • Breast Cancer • Oncology • Solid Tumor

Telomerase inhibitors TMPyP4 and BIBR 1532 show synergistic antitumor activity in combination with chemotherapeutic drugs. (PubMed, Sci Rep) - "We investigated the in vitro pharmacodynamic interactions of telomerase inhibitors (TMPyP4 and BIBR1532) with three anticancer drugs (cisplatin, doxorubicin, and paclitaxel) on a broad range of human cancer cell lines (MCF-7, MDA-MB-231, HeLa, U-118 MG, OVCAR-3, MCF-12A), selected based on the basal level of hTERT. This underscores the need for in vitro optimization to maximize the synergistic interaction of compounds. Combining genome-based medicine and drug screening using personalized models may fulfill the promise of precision medicine for every cancer type."

Journal • Oncology • TERT

Natural killer cells in combination with the inhibition of telomerase induced apoptosis in Acute Myeloid Leukemia cells. (PubMed, Biochem Biophys Rep) - "The combination of BIBR1532 and NK cells led to increased apoptosis, as indicated by the upregulation of the Bax and Bad genes, an increased Bax/Bcl-2 ratio, caspase 3/7 activity, Bax protein and a downregulation of mRNA expression levels of Bcl-2, Bcl-xl and decreased Bcl-2 protein. The findings of this study demonstrate that the concurrent application of BIBR1532 and NK cells promotes apoptosis and reduces proliferation by targeting apoptosis-related genes and proteins such as Bax and Bcl-2."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BAX • BCL2 • BCL2L1 • CASP3 • CASP7 • TERT

Telomerase and G-quadruplex dual-targeting chimera inhibits melanoma via telomere disruption (AACR 2025) - "Notably, the anti-melanoma effects of the chimeric compound outperform that of BIBR1532 or pyridostatin alone. Our study provides a more effective strategy for telomerase inhibition, and the telomerase and G4 dual-targeting chimera is a promising candidate for anticancer therapy."

Melanoma • Oncology • Solid Tumor

Dual-targeted microbubbles for atherosclerosis therapy: Inducing M1 macrophage apoptosis by inhibiting telomerase activity. (PubMed, Mater Today Bio) - "In this study, we developed a dual-target microbubble-delivery system (Ab-MMB1532) encapsulating BIBR1532, a telomerase inhibitor, for the targeted therapy of AS...In vivo studies further confirmed that Ab-MMB1532 effectively targets and accumulates within AS lesions, promoting M1 macrophage apoptosis through the inhibition of the TERT/NF-κB signaling axis, and significantly reducing plaque burden (25.4 % reduction vs. controls, p < 0.001). In summary, our findings suggest a novel approach for telomerase-targeted therapy in AS."

Journal • Atherosclerosis • Cardiovascular • CASP3 • TERT

How telomere maintenance affects endometriosis development: a preliminary study. (PubMed, Int J Med Sci) - "Materials and The telomere length of the postmenopausal endometria, eutopic endometria and their matched ectopic lesions in the proliferative and secretory phases was detected using fluorescence in situ hybridization (FISH) methods, and the effect of telomere length maintenance on the proliferation of endometrial cells derived from endometriotic patients was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with BIBR1532 treatment...The nomogram constructed based on telomere maintenance genes also displayed good predictive value. Telomere maintenance may contribute to the development of endometriosis, with several related genes involved."

Journal • Endometriosis • Gynecology • Infertility • Musculoskeletal Pain • Pain • Sexual Disorders • Women's Health

Exploiting the Achilles' heel of cancer through a structure-based drug-repurposing approach and experimental validation of top drugs using the TRAP assay. (PubMed, Mol Divers) - "Using a structure-based drug discovery framework, we screened the DrugBank database through a previously validated pharmacophore model for the FVYL pocket in the hTERT thumb domain, the established binding site of BIBR1532. As the top lead, Raltitrexed demonstrates the potential of repurposed drugs in telomerase-targeted therapies, offering a time and cost-effective strategy for advancing its clinical development. The study also provides a robust framework for future drug development, addressing challenges in targeting telomerase for anticancer therapy."

Journal • Oncology • TYMS

BIBR1532 inhibits proliferation and metastasis of esophageal squamous cancer cells by inducing telomere dysregulation. (PubMed, World J Gastrointest Oncol) - "BIBR1532 exerts anti-cancer effects on ESCC by inducing DDR through the ATR/CHK1 and ATM/CHK2 pathways and downregulating the expression of telomere-binding proteins."

Journal • Ataxia • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Squamous Cell Carcinoma • ATR • CHEK1 • CHEK2 • POT1 • TERF1 • TERF2 • TERT

Identification of novel inhibitors of cancer target telomerase using a dual structure-based pharmacophore approach to virtually screen libraries, molecular docking and validation by molecular dynamics simulations. (PubMed, J Biomol Struct Dyn) - "Due to the unavailability of a co-crystalized structure of BIBR1532 with the catalytic hTERT thumb domain, we utilized the molecular dynamics method to identify the precise binding site of the inhibitor...Additionally, cross-validated binding free energy calculations were performed using MM-PB(GB)SA methods followed by PCA and FEL characterization. The identified top lead compounds can be validated in vitro and taken forward for anticancer drug development."

Journal • Oncology

Telomerase-Responsive CRISPR System-Regulated Nanobomb for Triggering Research on Telomerase "Self-Detonation". (PubMed, ACS Appl Mater Interfaces) - "The targeted drug delivery nanobomb─BIBR1532@HSN/FQDNA/MUC1 aptamer (B@HDA) is prepared in this study based on hollow silica nanoparticles (HSN) and CRISPR systems...(3) In the tumor-bearing mouse model, B@HDA, combined with CRISPR, exhibits good biocompatibility and an obvious tumor ablation effect on MCF-7 tumors, suggesting potential application prospects across a wide range of cancer cell lines. In summary, the proposed nanobomb provides a tunable switch approach for the specific inhibition of telomerase and the reduction of tumor cell growth, representing a promising avenue for promoting senescence and treating cancer."

Journal • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • MUC1

Pan-cancer landscape of disulfidptosis across human tumors. (PubMed, Heliyon) - "Additionally, tumors with low disulfidptosis score exhibited higher sensitivity to a few small molecular compounds, e.g., Sabutoclax, PRIMA-1MET, BIBR-1532, and Elephantin. Knockdown of disulfidptosis gene GYS1 effectively hindered tumor progression. Collectively, our findings depict a pan-cancer map of disulfidptosis to inform functional and therapeutic research."

Journal • Pan tumor • Oncology • Solid Tumor

The mechanism of NF-κB-TERT feedback regulation of granulosa cell apoptosis in PCOS rats. (PubMed, PLoS One) - "Using letrozole and a high-fat diet, a PCOS rat model was established, along with a Lipopolysaccharide (LPS) -treated KGN cell inflammation model was established. NF-κB and TERT inhibitors (BAY 11-7082 and BIBR1532) were then administered to LPS-induced KGN cells...LPS-treated KGN cells demonstrated increased expression of inflammatory and pro-apoptotic factors, later restored post-treatment with NF-κB and TERT inhibitors (P are all less than 0.05). In conclusion, TERT may induce granulosa cell apoptosis by participating in the regulation of the NF-κB signaling pathway, thereby mediating the chronic inflammatory response of PCOS through downstream inflammatory factors IL-6 and TNF-α."

IO biomarker • Journal • Preclinical • Oncology • Polycystic Ovary Syndrome • BCL2 • CASP3 • IL6 • TERT • TNFA

Inhibition of Telomerase Activity by BIBR1532 Impairs Proliferation of Human Bladder Cancer Cells Through Induction of Replication Stress by Accumulation of G4-structures (DGU 2024) - "In this study, we evaluated the impact of the telomerase inhibitor BIBR1532 on BC cell lines' growth, alone or in combination with cisplatin. The presented results highlight the importance of telomerase in BC and as a promising target for therapy. The results with BIBR1532 suggest that this small molecule is a good candidate to target telomerase and to study the underlying molecular mechanisms."

Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CAV1

Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations. (PubMed, Bioorg Chem) - "In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem...Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change)...Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects."

Journal • Preclinical • Hematological Disorders • Oncology • JAK1 • STAT3 • TLR4

Inhibition of telomerase and the alternative lengthening telomere pathway induces cell death in Multiple Myeloma (IMW 2024) - "The MM cell line RPMI 8226 (CRM-CCL-155™) was treated with the telomerase inhibitor BIBR 1532 (200 µM) and the ALT inhibitor Trabectedin (4nM) to evaluate whether telomerase and ALT inhibition lead to cell death in MM. The results suggest that the MM cell line RPMI 8226 is most susceptible to the simultaneous inhibition of telomerase and ALT. This research represents a new opportunity for the future treatment of MM."

Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • Oncology

Designing, synthesis, and study of novel tetrahydro acridine analogs as telomerase inhibitors for the treatment of lung cancer (ACS-Fall 2024) - "The synthesized molecules were characterized by direct mass analysis, 1HNMR, 13CNMR, and X-ray crystallographic analysis. 5Flurouracil and BIBR 1532 were used in the in-vitro investigations as a reference standard.The investigation found that, in comparison to conventional telomerase inhibitors, the strategically engineered compounds give better results."

Lung Cancer • Oncology • Solid Tumor

Telomerase and mitochondria inhibition promote apoptosis and TET2 and ANMT3a expression in triple negative breast cancer cell lines. (PubMed, Bioimpacts) - "In addition, combination treatment was better than BIBR1532 and tigecycline alone. The inhibition of telomerase and mitochondria respiration caused intrinsic- and extrinsic- apoptosis and increased DNMT3a and TET2 expression and it could be utilized in breast cancer treatment."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • DNMT3A • TERT • TET2 • TP53

Targeting Telomerase: A Structure-Based Drug Design Approach for Investigating the Anti-Cancer Potential of FDA Approved Drugs and Novel Lead Candidates Using In-Silico and In-Vitro Assays (EACR 2024) - "Our study focuses on drug repurposing approach to investigate the therapeutic potential of FDA Approved drugs as well as identify novel leads that inhibit telomerase enzyme using a molecular dynamics-based structure guided approach followed by the experimental evaluation using an in-vitro TRAP assay.Material and Methods Due to unavailability of a co-crystalised structure of BIBR1532 with the catalytic hTERT thumb domain, we devised a Molecular dynamics-based method to identify the exact binding site of the inhibitor...PCA and FEL characterization further unveiled important interactions. These compounds are also undergoing evaluation using the in-vitro TRAP assay.Conclusion The study identified five potential clinically safe FDA-approved drugs which can be repurposed directly and four novel lead compounds against telomerase for advancing cancer therapeutics in future after further validation studies."

Preclinical • Oncology

LKB1 inhibits telomerase activity resulting in cellular senescence through histone lactylation in lung adenocarcinoma. (PubMed, Cancer Lett) - "The telomerase inhibitor BIBR1532 was beneficial for achieving the optimum curative effect of traditional chemotherapeutic drugs accompanied by the glycolysis inhibitor 2DG. These data reveal a new mechanism by which LKB1 regulates telomerase activity through lactylation-dependent transcriptional inhibition, and therefore, provide new insights into the effects of LKB1-mediated senescence in lung adenocarcinoma. Our research has opened up new possibilities for the creation of new cancer treatments."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • STK11 • TERT

BIBR1532 combined with radiotherapy induces ferroptosis in NSCLC cells and activates cGAS-STING pathway to promote anti-tumor immunity. (PubMed, J Transl Med) - "This study underscores the potential of BIBR1532 as an efficacious and safe radiosensitizer and radioimmunotherapy synergist, providing robust preclinical research evidence for the treatment of NSCLC."

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

Delineating the heterogeneity of senescence-induced-functional alterations in hepatocytes. (PubMed, Cell Mol Life Sci) - "In our study, we demonstrated that each senescence inducer activates a unique combination of senescence markers in PMH. Doxorubicin demonstrated the highest efficacy in inducing senescence, followed by cisplatin and H2O2, with no impact on apoptosis. Each inducer prompted DNA damage response and mitochondrial dysfunction, independent of MAPK/AKT."

Heterogeneity • Journal • Hepatology • Metabolic Disorders • CCL2 • CDKN1A • IL10

Identification of novel lead compounds and repurposing FDA approved drugs as telomerase inhibitors using structure-based drug designing approach and their evaluation using in-vitro and ex-vivo assays (AACR 2024) - "In our study, we have employed a molecular dynamics approach to validate the binding site of BIBR1532, an approved telomerase inhibitor in the hTERT thumb domain followed by a structure-based drug designing approach to repurpose FDA-approved drugs and identify novel lead compounds targeting the enzyme.Material and Due to the unavailability of a co-crystalized structure of BIBR1532 with the catalytic hTERT thumb domain, we employed a Molecular dynamics-based method to identify and validate the exact binding site of the inhibitor... The study identified five existing FDA-approved drugs in the market for other diseases as potential telomerase inhibitors alongside four novel compounds that can be used for the treatment of cancer in the future after further validation studies."

Preclinical • Oncology