AZD-2461 - CAS 1174043-16-3
Catalog number: 1174043-16-3
Category: Inhibitor
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AZD2461 is a novel and potent PARP inhibitor with lower affinity to P-glycoprotein. AZD2641 is currently in Phase I clinical study. The study is being conducted to see how it may work to treat solid tumors. The study will also assess the blood levels and action of AZD2461 in the body over a period of time and will indicate whether the drug has a therapeutic effect on solid tumors.
white solid powder
AZD2461; AZD 2461.
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1.The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models.
Oplustil O'Connor L;Rulten SL;Cranston AN;Odedra R;Brown H;Jaspers JE;Jones L;Knights C;Evers B;Ting A;Bradbury RH;Pajic M;Rottenberg S;Jonkers J;Rudge D;Martin NM;Caldecott KW;Lau A;O'Connor MJ Cancer Res. 2016 Oct 15;76(20):6084-6094. Epub 2016 Aug 22.
The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability.
2.Interactions Between Ataxia Telangiectasia Mutated Kinase Inhibition, Poly(ADP-ribose) Polymerase-1 Inhibition and BRCA1 Status in Breast Cancer Cells.
Węsierska-Gądek J;Heinzl S J Cancer Prev. 2014 Jun;19(2):125-36. doi: 10.15430/JCP.2014.19.2.125.
BACKGROUND: ;Cells harboring BRCA1/BRCA2 mutations are hypersensitive to inhibition of poly(ADP-ribose) polymerase-1 (PARP-1). We recently showed that interference with PARP-1 activity by NU1025 is strongly cytotoxic for BRCA1-positive BT-20 cells but not BRCA1-deficient SKBr-3 cells. These unexpected observations prompted speculation that other PARP-1 inhibitor(s) may be more cytotoxic towards SKBr-3 cells. In addition, interference with the DNA damage signaling pathway via (for instance) Ataxia telangiectasia mutated (ATM) kinase inhibition may induce synthetic lethality in DNA repair-deficient breast cancer cells and pharmacological interference with ATM activity may sensitize breast cancer cells to PARP-1 inactivation.;METHODS: ;We determined drug cytotoxicity in human MCF-7 and SKBr-3 breast cancer cells using the CellTiterGLO Luminescent cell viability assay and a Tecan multi-label, multitask plate counter to measure generated luminescence. Changes in cell cycle progression were monitored by flow cytometric measurement of DNA content in cells stained with propidium iodide.;RESULTS: ;Unlike NU1025, AZD2461, a new PARP-1 inhibitor, markedly reduced the numbers of living MCF-7 and SKBr-3 cells.
3.Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer.
Henneman L;van Miltenburg MH;Michalak EM;Braumuller TM;Jaspers JE;Drenth AP;de Korte-Grimmerink R;Gogola E;Szuhai K;Schlicker A;Bin Ali R;Pritchard C;Huijbers IJ;Berns A;Rottenberg S;Jonkers J Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8409-14. doi: 10.1073/pnas.1500223112. Epub 2015 Jun 22.
Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics.
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CAS 1174043-16-3 AZD-2461

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