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
3759 (aR)-RP-6306 (aR)-enantiomer of RP-6306 (Axon 3668); PKMYT1 inhibitor €180.00
2296 (S)-Crizotinib MTH1 inhibitor €85.00
1687 (±)-E-Homocamptothecin Potent topoisomerase I (Topo 1) inhibitor €120.00
2537 1,5-Isoquinolinediol PARP1 inhibitor and neuroprotective agent €50.00
1496 3-Aminobenzamide Competitive small molecule inhibitor of PARP €40.00
3476 5-NIdR Potent inhibitor of translesion DNA synthesis (TLS) €120.00
3039 ACY-241 Selective and orally available HDAC6 inhibitor €120.00
1529 AG 014699 PARP1 inhibitor €60.00
2269 AK 1 Potent inhibitor of SIRT with good selectivity for SIRT2 over SIRT1 and SIRT3 €90.00
2270 AK 7 Potent, brain-permeable and selective inhibitor of SIRT2 €90.00
2639 AMG 232 Potent, selective, and orally bioavailable MDM2-p53 inhibitor €120.00
3682 AMZ30 Potent, selective and covalent PME-1 inhibitor €130.00
3008 AOH1160 First-in-class, potent and orally available PCNA inhibitor €120.00
4030 AOH1996 Orally available PCNA inhibitor €140.00
2394 AR-42 HDAC inhibitor €125.00
5051 Axon Ligands™ Cell signaling and Oncology compound library Axon Ligands™ Cell signaling and Oncology compound library Inquire
5052 Axon Ligands™ Epigenetic compound library Axon Ligands™ Epigenetic compound library Inquire
2345 AZ 20 Potent, orally active and selective inhibitor of ATR protein kinase €105.00
4140 AZD0156 Selective and orally active ATM inhibitor €90.00
2241 AZD2461 PARP inhibitor with poor P-glycoprotein substrate qualities €95.00
3134 AZD6738 Potent, selective, orally active and bioavailable ATR kinase inhibitor €110.00
4068 AZD7648 DNA-PK inhibitor €90.00
1399 AZD7762 hydrochloride CHK inhibitor €60.00
2918 BAY 1895344 Potent, orally available and highly selective inhibitor of ATR protein kinase €100.00
3115 Belinostat HDAC inhibitor €70.00
3397 BG45 HDAC inhibitor (1, 2, 3 Selective) €80.00
2301 BIBR 1532 Potent and selective telomerase inhibitor inducing senescence in human cancer cells. €70.00
2462 BMH 21 Inhibitor of RNA Polymerase I (RNAP1) €95.00
3399 BML-210 HDAC inhibitor €80.00
2471 BRD 73954 Dual HDAC 6/8 inhibitor with excellent selectivity over the other HDACs €85.00

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