VE-821 / EMD Serono, Vertex - LARVOL DELTA

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

The Role of ATR Inhibitors in Ovarian Cancer: Investigating Predictive Biomarkers of Response. (PubMed, Cells) - "HGS cells had increased levels of RS (pRPA and γH2AX nuclear immunofluorescence), and elevated RS predicted sensitivity to VE-821 independently of the cell line subtype. These data suggest that functional assessment of RS biomarkers may be a better predictive biomarker of ATRi response than any single aberrant gene in ovarian cancer and potentially other cancers."

Biomarker • Journal • Ataxia • Immunology • Movement Disorders • Oncology • Ovarian Cancer • Primary Immunodeficiency • Solid Tumor • APOBEC3B • BRCA1 • RAD51 • TOPBP1 • TP53

CTPS1 IS A NOVEL THERAPEUTIC TARGET IN MYELOMA - SELECTIVE SMALL MOLECULE INHIBITION DELIVERS SINGLE AGENT ACTIVITY AND SYNERGISES WITH ATR INHIBITION (EHA 2022) - "The ATR inhibitor ceralasertib demonstrated additive or synergistic activity when combined with STP938 (Figure C)...Results were confirmed with a second ATR inhibitor (VE-821, Figure C)...These data suggest a model whereby myeloma cells with high background replication stress are sensitive to killing by single agent STP938, whereas cells with lower background replication stress are sensitised by STP938 to cell death induced by ATR inhibition (Figure D). STP938 will shortly enter clinical development for patients with late stage lymphoid neoplasms."

Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • CHEK1 • CHEK2

CHST11-mediated microenvironment events contribute to pulmonary fibrosis and cancer progression. (PubMed, FASEB J) - "By reversing the CHST11-IL6/IL1B-IRF8-CD80/CD86 mediated axis, we confirmed that VE821 and LY2603618 have the value of drug repurposing. Our study proves novel insight into how CHST11 contributes to cystic fibrosis and lung cancer by reprogramming the immune microenvironment."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Idiopathic Pulmonary Fibrosis • Immune Modulation • Immunology • Inflammation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CD86 • IL1B • IL6 • IRF8

Utilizing 7-azaindoles, 2,7-diazaindoles, and 1H‑pyrazoles as core structures for novel cancer chemosensitizers (AACR 2022) - "All the compounds alone or in combination with cisplatin were screened against panel of nine cancer cell lines and one healthy cell line...Besides, both structures could be used for a glioblastoma treatment as temozolomide sensitizers. More research is currently ongoing to fully exploit potential of these compounds."

Astrocytoma • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • FLT4 • TP53

Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment. (PubMed, Cell Genom) - "We find that missense- but not frameshift mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). The in vivo validated hits include emetine and ouabain, compounds which are approved for non-cancer indications and which perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • ARID1A • BRCA2

The RNA-binding protein GRSF1 promotes hepatocarcinogenesis via competitively binding to YY1 mRNA with miR-30e-5p. (PubMed, J Exp Clin Cancer Res) - "This study revealed the interaction network among GRSF1, YY1 and miR-30e-5p, providing new insight into HCC pathogenesis, and indicated that VE821 may serve as a novel agent with potential for HCC treatment through inhibition of the GRSF1/YY1 axis."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • MIR30E

Olaparib-induced Apoptosis Through EBNA1-ATR-p38 MAPK Signaling Pathway in Epstein-Barr Virus-positive Gastric Cancer Cells. (PubMed, Anticancer Res) - "Olaparib treatment led to different cellular responses depending on EBV infection in gastric cancer cell lines. These results provide new insights into the mechanism of olaparib-induced apoptosis in gastric cancer cells and suggest that EBV infection should be considered when developing new potential therapeutic agents for gastric cancer."

Journal • Ataxia • Epstein-Barr Virus Infections • Gastric Cancer • Gastrointestinal Cancer • Immunology • Infectious Disease • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • CASP3