VE-821 / EMD Serono, Vertex - LARVOL DELTA

Common DNA Damage Response Factors Required for Cellular Resistance to Inhibitors for the Ataxia Telangiectasia and Rad3-Related Checkpoint Kinase in Hematopoietic Cells. (PubMed, Biomolecules) - "We then compared cellular sensitivity patterns of the known ATR inhibitor, VE-821, and the potential ATR inhibitors, SPK67 and SPK98, in 24 types of mutants deficient in genome maintenance systems and found that RAD17/-, FEN1-/-, and POLB-/- cells exhibited hypersensitivity to all these drugs...These results suggest that, although ATR inhibition causes DNA damage, impaired checkpoint function suppresses the appropriate activation of DNA damage signaling pathways, thereby leading to cell death. This study is the first to demonstrate the importance of Rad17, Fen1, and Polymerase β in cellular tolerance to ATR inhibition in hematopoietic cells."

Journal • Ataxia • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Movement Disorders • Oncology • Primary Immunodeficiency • ATR • CHEK1 • FEN1 • POLG2 • RAD17

Septins regulate kinase-inhibitor induced micron-scale vacuolation. (PubMed, Exp Cell Res) - "FCF inhibited vacuolation induced by SB202190, PIKFYVE inhibitors and VE-821. Unlike bafilomycin, which inhibits vacuolation with parallel blockade of autophagic proteolysis, FCF mediated suppression of vacuoles doesn't involve accumulation of autophagy markers. The role of septins in micron scale vacuolation may be linked to their role in endosome maturation and septins may contribute towards the cell-type specificity of micron-scale vacuolation."

Journal • Targeted Protein Degradation • CD63 • SEPTIN7 • SEPTIN9

Differential modulation of haematopoietic and oxidative injury by PARP-1 and ATR kinase inhibition in a murine model of acute irradiation. (PubMed, PLoS One) - "While administering PARP inhibitors following the exposure to ionising radiation was found to reduce the severity of the condition experienced by the subject, as a result of acute radiation syndrome, the same was not seen when the treatment with ATR inhibitors was given to affected subjects. The results of this study show the significance of administering therapeutic agents at the right time to stop the injury to normal cells when DNA repair pathways are activated by exposure to ionising radiation."

Journal • Preclinical • Leukopenia • Oncology

Moderate hyperthermia as adjuvant therapy for Pancreatic Ductal Adenocarcinoma (PDAC): Pleiotropic effects may modulate drug cytotoxicity Free (AACRPanCa 2025) - "Here, we evaluate the effects of moderate HT (41.5 °C, 4h) on the S-phase and its implications on the efficacy of gemcitabine (GEM) in pancreatic cancer cell lines...ATR inhibition with VE-821 or ATM inhibition (InSolution®) could not restore the decreased EdU incorporation in all cell lines, suggesting that the S-phase attenuation may not be entirely caused through excessive ATR/ATM-signaling...Our findings underscore the complexity and potential cell line–specific impact of HT on nucleoside uptake and DNA replication, with important implications for chemotherapeutic efficacy. Careful drug selection and optimization of treatment timing will be essential to harness potential synergy in combinatorial regimens."

Clinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • SLC29A1 • TP53BP1

Co-Targeting SFKs and DNA Damaging Chemotherapy Drugs as a Novel Therapeutic Strategy in SCLC (IASLC-WCLC 2025) - "We selected drugs either currently used in SCLC patients (in first- or second-line treatments) or that might target the DNA damage repair (DDR) in combination with Dasatinib: lurbinectedin, topotecan, etoposide, cisplatin and VE-821. Tumor volumes were significantly reduced compared to single drugs when mice were treated in vivo . Thus, combining Dasatinib with Lurbinectedin or Topotecan represent two novel therapeutic strategies for SCLC treatment."

IO biomarker • Hematological Malignancies • Lung Cancer • Small Cell Lung Cancer • Solid Tumor

DDR kinase inhibition causes hypersensitivity to Taxol through caspase-3 activation. (PubMed, Biochem Biophys Res Commun) - "Pharmacological inhibitors, KU55933 (ATM), NU7441 (DNA-PK), and VE821 (ATR), also sensitized V79, CHO, and U2OS human cancer cells to Taxol. These findings suggest that ATM, ATR, and DNA-PK not only facilitate DNA repair but also suppress Taxol-induced apoptosis via caspase-3. Their inhibition may represent a promising strategy to boost their efficacy of Taxol and potentially enhance responses to radiation therapy through combined targeting of mitotic stress and DDR pathways."

Journal • Immunology • Oncology • CASP3 • CASP7

Disruption of ATR Signaling by Epstein-Barr Virus Latent Membrane Protein 1 Sensitizes Nasopharyngeal Carcinoma Cells to Cisplatin. (PubMed, J Med Virol) - "Inhibition of ATR (VE821 or AZD6738), but not ATM (KU55933 or AZD0156), phenocopied the G1 arrest and hypersensitivity. Publicly available RNA-sequencing data from microdissected NPC tumors showed that LMP1 expression in the primary tumors was the lowest in cisplatin-treated patients that experienced recurrence. These findings could have clinical significance in stratifying NPC patients such that tumors with limited or variable LMP1 expression might benefit from ATR inhibitor therapy."

Journal • Epstein-Barr Virus Infections • Immunology • Infectious Disease • Nasopharyngeal Carcinoma • Oncology • Solid Tumor

Kinase Inhibitor-Induced Cell-Type Specific Vacuole Formation in the Absence of Canonical ATG5-Dependent Autophagy Initiation Pathway. (PubMed, Mol Cell Biol) - "A screen for modulators of SB202190-induced vacuolation revealed molecules including multi-kinase inhibitor sorafenib as inhibitors of vacuolation and sorafenib co-treatment enhanced cytotoxicity of SB202190. To identify the factors determining the cell-type specificity of vacuolation induced by SB-compounds and VE-821, we compared the transcriptomics data from vacuole-forming and non-vacuole-forming cancer cell lines and identified a gene expression signature that may define sensitivity of cells to these small-molecules. Further analyses using small molecule tools and the gene signature discovered here, could reveal novel mechanisms regulating this interesting anti-cancer phenotype."

Journal • Oncology • ATG5 • MAPK1 • MAPK11 • MAPK14

CRM1 regulates androgen receptor stability and impacts DNA repair pathways in prostate cancer, independent of the androgen receptor (PCF 2024) - "Drug combination assays were performed for Selinexor with ATR inhibitor VE821, ATM inhibitor AZ32, PARP inhibitor Olaparib, and DNA-PK inhibitor M3814. CRM1 can affect prostate cancer growth by regulating the stability of the androgen receptor and impacts DNA repair in prostate cancer cells independent of the androgen receptor."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CDC37

ATR, CHK1 and WEE1 inhibitors cause homologous recombination repair deficiency to induce synthetic lethality with PARP inhibitors. (PubMed, Br J Cancer) - "Our data indicate that, rather than acting via abrogation of cell cycle checkpoints, ATR, CHK1 and WEE1 inhibitors cause an HRD phenotype and hence "induced synthetic lethality" with PARPi."

Journal • Synthetic lethality • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • HRD • RAD51

Circular PVT1 exerts a pro-tumorigenic and immune-suppressor functions in Acute Myeloid Leukemia (EACR 2024) - "Moreover, we combined circPVT1 silencing with ATR inhibitor(VE-821) or PARP1/2 inhibitor (talazoparib) on both cell lines. Moreover, circPVT1-KD potentiated the antiproliferative effect of ATR or PARP inhibitors on AML cell lines. Finally, circPVT1-KD silencing in AML cells enhanced T-cell cytotoxic capacity, with an increase of granzyme B, in co-culture experiments of leukemic and CD3+ T cells, but not in the presence of selected CD8+ T cells, indicating an indirect regulatory role mediated by other T cell subpopulations.Conclusion These results reported an involvement of circPVT1 in the DNA damage response, along with a role in drug response and resistance in AML and in the crosstalk between leukemic cells and the tumor microenvironment."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD8 • GZMB • PVT1

COMBINED INHIBITION OF CTPS1 AND ATR IS A METABOLIC VULNERABILITY IN P53-DEFICIENT MYELOMA CELLS (EHA 2024) - "To this end, we evaluated the efficacy of CTPS1 and ATR inhibition using clinical-grade specificpharmacologic inhibitorsInhibition of CTPS1 alone or in combination with ATR was assessed using STP-B, VE-821 or AZD6738, in vitro inhuman myeloma cell lines (HMCLs) and in isogenic TP53+/+, TP53-/-, TP53R175H XG7 and NCI-H929 HMCLs,ex vivo in samples from 17 patients with myeloma (with or without del17p), and in vivo in TP53-/- NCI-H929xenografted miceUsing (sc)RNA-seq analysis, we identified that CTPS1, which encodes a rate-limiting enzyme for CTP synthesisthat is essential for DNA and RNA synthesis in lymphoid cells, was over-expressed in samples from patientswith a low p53 functional transcriptional score (synonymous with deletion and/or mutation in TP53 gene,Durand et al Blood, 2023) or a high proliferation rate (MKI67++), TP53Abn myeloma cells overexpressingMKI67. In conclusion, our results show that the dual targeting of CTPS1 and ATR induces mitotic catastrophe in..."

Hematological Malignancies • Multiple Myeloma • Oncology • CTPS1 • MKI67

Pharmacological degradation of ATR induces antiproliferative DNA replication stress in leukemic cells. (PubMed, Mol Oncol) - "It is derived from the ATR inhibitor VE-821 and recruits the E3 ubiquitin-ligase component cereblon to ATR...This mechanism provokes DNA replication catastrophe and augments anti-leukemic effects of the clinically used ribonucleotide reductase-2 inhibitor hydroxyurea...Treatment of wild-type but not of cereblon knockout cells with Abd110 stalls their proliferation which verifies that ATR elimination is the primary mechanism of Abd110. Altogether, our findings demonstrate specific anti-leukemic effects of an ATR PROTAC."

Journal • Ataxia • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Oncology • Primary Immunodeficiency • Targeted Protein Degradation • CRBN

Depletion of Labile Iron Induces Replication Stress and Enhances Responses to Chemoradiation in Non-Small-Cell Lung Cancer. (PubMed, Antioxidants (Basel)) - "Depletion of the LIP in non-small-cell lung cancer cell lines using the doxycycline-inducible overexpression of the ferritin heavy chain (Ft-H) (H1299 and H292), or treatment with deferoxamine (DFO) (H1299 and A549), inhibited cell growth and decreased clonogenic survival...The Ft-H and DFO treatment also sensitized H1299 to VE-821, an inhibitor of ataxia telangiectasis and Rad2-related (ATR) kinase, highlighting the potential of LIP depletion, combined with DNA damage response modifiers, to alter lung cancer cell responses...Importantly, the Ft-H and DFO sensitized both H1299 and A549 to chemoradiation in vitro, and Ft-H overexpression increased the efficacy of chemoradiation in vivo in H1299. These results support the hypothesis that the depletion of the LIP can induce genomic instability, cell death, and potentiate therapeutic responses to chemoradiation in NSCLC."

Journal • Ataxia • Lung Cancer • Movement Disorders • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FEN1

Abrogation of ATR function preferentially augments cisplatin-induced cytotoxicity in PTEN-deficient breast cancer cells. (PubMed, Chem Biol Interact) - "We demonstrate PTEN dysfunction promotes the killing effect of ATR blockade through the use of RNA interference for PTEN and a highly selective ATR inhibitor VE-821, and certify that VE-821 (1.0 μmol/L) aggravates cytotoxicity of cisplatin on breast cancer cells, especially PTEN-null MDA-MB-468 cells which show more chemoresistance than PTEN-expressing MDA-MB-231 cells. The increased cytotoxic activity is tied to the enhanced poly (ADP-ribose) polymerase (PARP) cleavage and consequently cell death due to the decrease in phosphorylation levels of checkpoint kinases 1 and 2 (CHK1/2), the reduction of radiation sensitive 51 (RAD51) foci and the increase in phosphorylation of the histone variant H2AX (γ-H2AX) foci (P < 0.05) as well. Together, these findings suggest combination therapy of ATR inhibitor and cisplatin may offer a potential therapeutic strategy for breast tumors."

Journal • Ataxia • Breast Cancer • Gene Therapies • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Triple Negative Breast Cancer • CHEK1 • PTEN • RAD51

Silencing linear PVT1 isoforms and CIRCPVT1 sensitezed AML Cell Line to ATR inhibitor (VE-821) (SOHO Italy 2023) - No abstract available

Preclinical • Acute Myelogenous Leukemia • PVT1

The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin. (PubMed, Transl Oncol) - "Our results suggested VE-821 sensitized GC cells to cisplatin via reversing DDR activation. And VE-821 treatment may be a promising therapeutic strategy for GC patients with cisplatin resistance."

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

Comprehensive analysis of angiogenesis pattern and related immune landscape for individual treatment in osteosarcoma. (PubMed, NPJ Precis Oncol) - "OS patients with high ANGscore might be resistant to uprosertib, and be sensitive to VE821, AZD6738 and BMS.345541. In conclusion, we established a novel ANGscore system by comprehensively analysing the expression pattern of angiogenesis genes, which can accurately differentiate the prognosis and immune characteristics of OS populations. Additionally, the ANGscore can be used for patient stratification during immunotherapy, and guide individualized treatment strategies."

IO biomarker • Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • IFNG

Synergistic anticancer activity of combined ATR and ribonucleotide reductase inhibition in Ewing's sarcoma cells. (PubMed, J Cancer Res Clin Oncol) - "Our study reveals that combined targeting of ATR and RNR was effective against Ewing's sarcoma in vitro and thus rationalises an in vivo exploration into the potential of combining ATR and RNR inhibitors as a new strategy for the treatment of this challenging disease."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • BBC3 • CASP3 • CASP7 • CDKN1A • TP53

The Combination of the PARP Inhibitor Olaparib and the ATR Inhibitor VE-821 Selectively Targets ATM-Deficient Lung Cancer Cells (IASLC-WCLC 2019) - "We show that olaparib acts as a cytostatic agent in ATM-deficient lung cancer cells, inducing a reversible and temporary growth arrest in G2 phase. Only when combined with the ATR inhibitor VE-821 was cell death observed and only in ATM-deficient cells. Our data suggest that patients with ATM-deficient lung cancer could benefit from combinatorial treatment with PARP and ATR inhibitors."

PARP Biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

The ATR Inhibitor VE-821 Enhances the Radiosensitivity and Suppresses DNA Repair Mechanisms of Human Chondrosarcoma Cells. (PubMed, Int J Mol Sci) - "Pre-treatment with the PARPis Olaparib or Veliparib, the ATMi Ku-55933, and the ATRi VE-821 resulted in a dose-dependent reduction in viability, whereas VE-821 has the most efficient response. At the gene expression and at the protein expression/phosphorylation level, we were able to demonstrate the preservation of DNA damage after combined treatment. The present data showed that the combined treatment with ATMi VE-821 increases the radiosensitivity of human chondrosarcoma cells in vitro and significantly suppresses efficient DNA repair mechanisms, thus improving the efficiency of radiotherapy."

Journal • Oncology • Sarcoma • Solid Tumor

Systematic analysis of virus nucleic acid sensor DDX58 in malignant tumor. (PubMed, Front Microbiol) - "Finally, according to the expression of DDX58 indicated potential sensitive drugs such as Cediranib, VE-821, Itraconazole, JNJ-42756493, IWR-1, and Linsitinib. In conclusion, we had gained new insights into how DDX58 might contribute to tumor development, and DDX58 could be used as an immune-related biomarker and as a potential immunotherapeutic target for COVID-19 infected cancer patients."

IO biomarker • Journal • Tumor mutational burden • Infectious Disease • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • Solid Tumor • Targeted Protein Degradation • DDX58 • MSI

CTPS1 Is a Novel Therapeutic Target in Multiple Myeloma That Synergizes with Inhibition of ATR, CHEK1 or WEE1 (ASH 2022) - "Combining CTPS1 inhibition by STP938 with inhibitors of different components of the DDR pathway demonstrated strong synergy, with consistent results observed when combining STP938 with inhibitors of either ATR (ceralasertib, VE-821), CHEK1 (rabusertib, SRA737) or WEE1 (adavosertib) (Figure B). The ability of the homologous CTPS2 enzyme to compensate for CTPS1 loss outside the hematopoietic system suggests that inhibition of CTPS1 will not be associated with significant non-hematological toxicity. Clinical evaluation of STP938 in lymphoid malignancies will start in Q3 this year."

Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • ANXA5 • CHEK2

Differences in Durability of PARP Inhibition by Clinically Approved PARP Inhibitors: Implications for Combinations and Scheduling. (PubMed, Cancers (Basel)) - "To investigate if such intense schedules are necessary, we determined the durability of PARP inhibition up to 72 h after a 1 h pulse of 1 µM of five of the approved PARPi, rucaparib, olaparib, niraparib, talazoparib and pamiparib, in IGROV-1 and ES-2 (human ovarian cancer) cells. Olaparib and niraparib enhanced VE-821 cytotoxicity only in co-exposed cells and not in sequential exposures. These data have clinical implications for the scheduling of PARPi as a monotherapy and in combination with ATR inhibitors and other cytotoxic drugs."

Journal • Oncology • Ovarian Cancer • Solid Tumor

Determining the Potential of DNA Damage Response (DDR) Inhibitors in Cervical Cancer Therapy. (PubMed, Cancers (Basel)) - "We have directly compared, for the first time, the cytotoxicity of four DDR inhibitors (rucaparib/PARPi, VE-821/ATRi, PF-477736/CHK1i and MK-1775/WEE1i) as single agents, and in combination with cisplatin and radiotherapy (RT) in a panel of CC cells. In mice, cisplatin-induced acute kidney injury was associated with oxidative stress and PARP activation and was prevented by rucaparib. Therefore, while all inhibitors investigated may increase the efficacy of CRT, the greatest clinical potential of rucaparib may be in limiting kidney damage, which is dose-limiting."

Journal • Acute Kidney Injury • Cervical Cancer • Nephrology • Oncology • Renal Disease • Solid Tumor • CHEK1