AZD2461 / AstraZeneca - LARVOL DELTA

Computational design of PARP-1 inhibitors: QSAR, molecular docking, virtual screening, ADMET, and molecular dynamics simulations for targeted drug development. (PubMed, SAR QSAR Environ Res) - "Molecular docking studies revealed that several new compounds exhibited strong interactions with key amino acids GLY 227A, MET 229A, PHE 230A, and TYR 246A within the PARP-1 active site, similar to those observed in reference inhibitors Olaparib and AZD2461. Then, the top-ranked compound's (3a) ligand-protein complex underwent a 200 ns molecular dynamics (MD) simulation, confirming stable binding and revealing a robust set of intermolecular interactions maintained under physiological conditions."

Journal • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • HRD

PARP1 Characterization as a Potential Biomarker for BCR::ABL1 p190+ Acute Lymphoblastic Leukemia. (PubMed, Cancers (Basel)) - "In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR::ABL1 p190+ ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current gold standard in medical care. Overall, we demonstrate the effectiveness of PARPi in the treatment of BCR::ABL1 p190+ ALL cell models and that PARP1 is differentially expressed in patient samples. We hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in clinical practice."

Biomarker • Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • PARP1

The impairment of DDR reduces XBP1s, further increasing DNA damage, and triggers autophagy via PERK/eIF2alpha in MM and IRE1alpha/JNK1/2 in PEL cells. (PubMed, Biochem Biophys Res Commun) - "Indeed, PARP and CHK1 inhibition by AZD2461 and UCN-01, by downregulating c-Myc, reduced the expression of XBP1s, constitutively expressed in these cells, and upregulated CHOP. Interestingly, given the role of XBP1s in regulating DDR, BRCA-1 expression level was reduced, exacerbating DNA damage. Finally, DDR/UPR interplay activated a pro-survival autophagy via PERK/eIF2alpha axis in MM and IRE1alpha/JNK axis in PEL cells, since in the latter case PERK/eIF2alpha activation could be prevented by KSHV that, as other herpesviruses, tries to avoid the blocks of protein translation that this pathway may induce."

Journal • Oncology • BRCA • BRCA1 • MAPK8 • MYC • UCN

VPA and TSA Interrupt the Interplay between mutp53 and HSP70, Leading to CHK1 and RAD51 Down-Regulation and Sensitizing Pancreatic Cancer Cells to AZD2461 PARP Inhibitor. (PubMed, Int J Mol Sci) - "HDACi have been also reported to increase the cytotoxicity of DNA-damaging agents, such as radiation or cisplatin. Moreover, VPA and to a lesser extent TSA reactivated wtp53 in these cells, which contributed to CHK1 and RAD51 reduction. These findings suggest that the combination of HDACi and PARPi might improve the treatment of pancreatic cancer, which remains one of the most aggressive and therapy-resistant cancers."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CHEK1 • RAD51

DNA damage triggers an interplay between wtp53 and c-Myc affecting lymphoma cell proliferation and KSHV replication. (PubMed, Biochim Biophys Acta Mol Cell Res) - "Here we show that the PARP-1/2/3 inhibitor AZD2461 in combination with the CHK1 inhibitor UCN-01 altered the DNA damage response and reduced cell proliferation in PEL cells, an aggressive B cell lymphoma highly resistant to chemotherapies. Finally, we found that the pharmacological or genetic inhibition of p21 counteracted the viral lytic cycle activation and further reduced PEL cell proliferation, suggesting that it could induce a double beneficial effect in this setting. This study unveils that, therapeutic approaches, based on the induction of DNA damage and the reduction of DNA repair, could be used to successfully treat this malignant lymphoma."

Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MYC • RAD51

Anticancer effect of AZD2461 PARP inhibitor against colon cancer cells carrying wt or dysfunctional p53. (PubMed, Exp Cell Res) - "Moreover, AZD2461 improved the reduction of cell proliferation by low dose radiation (IR) in wtp53 cancer cells, in which a down-regulation of BRCA-1 occurred. AZD2461 did not affect cell proliferation of mutp53 colon cancer cells also in combination with low dose radiation, suggesting that only wt p53 or p53 null colon cancer cells could benefit AZD2461 treatment."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2

Response of Breast Cancer Cells to PARP Inhibitors Is Independent of BRCA Status. (PubMed, J Clin Med) - "Especially JIMT1, which is known to be resistant to trastuzumab, was responsive to Talazoparib at 0.002 µM...In contrast, a BRCA-mutant TNBC line, HCC1937, was less sensitive to Talazoparib, Niraparib, Rucaparib, and not responsive to Olaparib. Other PARPi such as UPF1069, NU1025, AZD2461, and PJ34HCl also showed potent inhibitory activity in specific breast cancer cells. Our data suggest that the benefit of PARPi therapy in breast cancer is beyond the BRCA-mutations, and equally effective on metastatic TNBC and ER-/HER2+ breast cancers."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • ER • HER-2

PARP inhibitors affect growth, survival and radiation susceptibility of human alveolar and embryonal rhabdomyosarcoma cell lines. (PubMed, J Cancer Res Clin Oncol) - "This study suggests that the combined exposure to PARPi and IR might display a role in the treatment of RMS tumours compared with single-agent exposure, since stronger cytotoxic effects are induced, and compensatory survival mechanisms are prevented."

Journal • PARP Biomarker • Biosimilar • Oncology • Sarcoma • Solid Tumor

[F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging. (PubMed, Mol Imaging Biol) - "Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents."

Journal • Oncology • PARP • PARP1

Influence of Onconase in the Therapeutic Potential of PARP Inhibitors in A375 Malignant Melanoma Cells. (PubMed, Biochem Pharmacol) - "One of the most used by clinicians is olaparib, that, however, showed again cancer resistance in patients. Moreover, we underline that A375 cells treated for a prolonged time with AZD2461 were definitely more susceptible than parental A375 cells to the pro-apoptotic action of ONC. Considering also the different inhibitory effects of the two drugs on TNF-α gene expression and NF-kB DNA-binding, the tuning of their combined delivery to the A375 tumor cell line might open a promising scenario for future therapeutic applications devoted to defeat human melanoma."

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Synthesis and evaluation of an AZD2461 [F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant. (PubMed, Bioorg Chem) - "Poly(ADP-ribose)polymerase-1 inhibitor (PARPi) AZD2461 was designed to be a weak P-glycoprotein (P-gp) analogue of FDA approved olaparib. Our work led to the identification of several high-affinity PARPi, including AZD2461 congener 9e (PARP-1 IC = 3.9 ± 1.2 nM), which was further evaluated as a potential F-PET brain imaging probe. However, despite the similar molecular scaffolds of 9e and AZD2461, our studies revealed non-appreciable brain-uptake of [F]9e in non-human primates, suggesting AZD2461 to be non-CNS penetrant."

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Novel poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, AZD2461, down-regulates VEGF and induces apoptosis in prostate cancer cells (PubMed, Iran Biomed J) - "VEGF mRNA levels in PC-3 cells significantly decreased compared to adjusted untreated cells (p < 0.05) in all measured times while displaying different alteration patterns in DU145 cells (p < 0.05). AZD2461 suppresses the growth of prostate tumor cells since AZD2461 monotherapy could prove efficacious, especially against cells not expressing PTEN besides activating the possible apoptosis-independent cell death pathways."

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Topical 2'-Hydroxyflavanone for Cutaneous Melanoma. (PubMed, Cancers (Basel)) - "2HF enhanced sunitinib (an MEK and PDGFR-β inhibitor) and AZD2461 (a PARP1 inhibitor) cytotoxicity. We conclude that 2HF-PLO gel maybe useful for topical therapy of cutaneous metastases of melanoma and could enhance theantineoplastic effects of sunitinib and PARP1 inhibitors. The mechanism of action of 2HF inmelanoma overlaps with RLI76 inhibitors."

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ABCB1 ATTENUATES THE BRAIN PENETRATION OF THE PARP INHIBITOR AZD2461. (PubMed, Mol Pharm) - "Poly (ADP-ribose) polymerase (PARP) inhibitors are a relatively new class of anticancer agents that have attracted attention for treatment of glioblastoma because of their ability to potentiate temozolomide chemotherapy. We show that AZD2461 has a low oral bioavailability, although not affected by P-gp and BCRP. Together, these findings are not in favor of further development of AZD2461 for treatment of glioblastoma."

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Induction of apoptosis and modulation of homologous recombination DNA repair pathway in prostate cancer cells by the combination of AZD2461 and valproic acid. (PubMed, EXCLI J) - "Both mRNA and protein levels of Rad51 and Mre11 were significantly decreased in PC-3 cells co-treated with VPA+AZD2461 while enhanced H2AX phosphorylation was found in PC-3 cells after 12 and 24 hours of co-treatment (p<0.05). Our findings established a preclinical rationale for selective targeting of HR repair pathways by a combination of VPA and AZD2461 as a mechanism for reducing the HR pathway sufficiency in PTEN-mutated prostate cancer cells."

BRCA Biomarker • Journal • PARP Biomarker

Mild antagonistic effect of Valproic acid in combination with AZD2461 in MCF-7 breast cancer cells. (PubMed, Med J Islam Repub Iran) - "The mechanism responsible for drugs combination was not of synergism or addition. Determining the type of involved cell death mechanisms might be followed in further studies."

Combination therapy • Journal • PARP Biomarker