DNA-damage Response

Nuclear DNA is undoubtedly the most precious component of a cell. It is not surprising therefore that any kind of damage that introduces a discontinuity in the DNA double helix elicits a prompt cellular reaction. The DNA damage response (DDR) provides an intrinsic biological barrier against the duplication and partitioning of damaged DNA into daughter cells and impedes the propagation of corrupted genetic information[1]. When maintenance of genome integrity fails, it might lead to programmed cell death (apoptosis), or genomic instability (GIN), which in turn can cause cell transformation and oncogenesis[2]. Among the Serine and Threonine specific kinases, a number of them is involved in the processes that play a significant role in the DDR. For example, Ataxia telangiectasia mutated (ATM) kinase recognizes and signals to double-strand breaks (DSB), which are among the most critical lesions in chromosomal DNA[3],[4]. ATM is present in the nucleus as an inactive dimer or oligomer, and is activated in response to DSBs in a process that involves autophosphorylation. This causes a dissociation of the dimer to form active monomeric forms, which are able to initiate the phosphorylation of many intermediates, such as p53 and the checkpoint kinase Chk2, which are involved in DNA repair and cell-cycle control[5]. Similar to ATM, the ataxia-telangiectasia and Rad3-related (ATR) protein and the DNA-activated protein kinase (DNA-PK) play an important role in responding to agents and extracellular stress that threaten the DNA replication process[6]. Interestingly, a normal and robust checkpoint pathway is thought to be a mechanism of resistance to chemotherapy. As a result, ATR-Chk1 pathway components are considered promising therapeutic targets. In particular, inhibition of ATR-Chk1 pathway components could potentially enhance the effectiveness of replication inhibitors[7].

[1] Living on a break: cellular senescence as aDNA-damage response. F d'Adda di Fagagna. Nature Reviews Cancer 2008, 8, 512-522.
[2] Cell-cycle checkpoints and cancer. Kastan, M. B. & Bartek, J. Nature 2004, 432, 316–323.
[3] DNA-PK, the DNA-activated protein kinase, is differentially expressed in normal and malignant human tissues. U Moll, R Lau, MA Sypes, MM Gupta, CW Anderson. Oncogene 1999, 18, 3114-3126.
[4] ATM and the DNA damage response. Workshop on ataxia-telangiectasia and related syndromes. Lavin MF, Delia D, Chessa L.EMBO Rep. 2006, 7, 154–160.
[5] DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Bakkenist CJ,KastanMB. Nature. 2003, 421, 499-506.
[6] ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses. J Yang, Y Yu, H Hamrick, PJ Duerksen-Hughes. Carcinogenesis 2003, 24, 1571-1580.
[7] Prospects for the Use of ATR Inhibitors to Treat Cancer. JM Wagner, SH Kaufmann. Pharmaceuticals 2010, 3, 1311-1334.

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Axon ID Name Description From price
2016 NSC 319726 Reactivator of the p53 mutant p53R175 €95.00
1402 NSC 348884 NPM inhibitor €120.00
2564 NSC 59984 Activator of p53 that restores WT p53 signaling via p73 activation €95.00
3277 NSC194598 p53 DNA-binding inhibitor €130.00
2966 NSC745887 DcR3 inhibitor €95.00
1370 NU 1025 PARP inhibitor €80.00
1463 NU 7441 DNA-PK inhibitor €40.00
2599 NVP-TNKS656 Selective and orally active TNKS inhibitor and antagonist of Wnt pathway activity €95.00
1464 Olaparib PARP inhibitor €50.00
2843 OSS-128167 Selective SIRT6 inhibitor €125.00
3152 PAWI-2 Inhibitor which targets both Wnt signaling and ATM/p53 €120.00
1853 PCI 34051 HDAC8 Inhibitor €90.00
3795 PDD00017273 First-in-class, selective and cell-active PARG inhibitor €90.00
1379 PF 477736 CHK1 inhibitor €70.00
2690 PHA-767491 Dual CDC7/CDK9 kinase inhibitor €95.00
1871 Pifithrin-α hydrobromide Inhibitor of p53 protein €95.00
3051 Pifithrin-β Inhibitor of p53 protein; Condensation product of Pifithrin-α €95.00
2488 Piperlongumine Natural alkaloid with potent cytotoxic activity €65.00
2965 PNR-7-02 Potent inhibitor of human DNA polymerase η €125.00
2420 PTC 209 Inhibitor of the canonical self-renewal regulator BMI-1 €125.00
4076 Pyridostatin hydrochloride G-quadruplex DNA stabilizing agent Inquire
1801 Pyroxamide HDAC1 Inhibitor €90.00
1911 RAD51 inhibitor B02 Inhibitor of RAD51 €95.00
2299 Remodelin Potent NAT 10 inhibitor that mediates nuclear shape rescue in laminopathic cells via microtubule reorganization €90.00
2195 RGFP 966 HDAC3 specific inhibitor €85.00
1885 RI-1 Inhibitor of the central recombination protein RAD51 €95.00
2009 RITA Activates p53 through inhibition of MDM2 €105.00
3668 RP-6306 First-in-class, potent, selective, and orally bioavailable PKMYT1 inhibitor €140.00
2584 RS-1 Enhancer of CRISPR-based genome editing and HDR/RAD51 €85.00
3113 Rucaparib camsylate PARP1 inhibitor €90.00

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