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
2704 Salermide Potent inhibitor of SIRT1 and SIRT2 €95.00
2495 Santacruzamate A Picomolar level HDAC2 inhibitor with little inhibition of HDAC4 and HDAC6 €85.00
2741 SAR405838 MDM2-p53 inhibitor €125.00
1777 SB 939 HDAC inhibitor (1, 2, 4 Selective) €95.00
3954 SBI-797812 Orally active NAMPT activator €130.00
2244 SCH 529074 Small molecule activator of mutant p53. €120.00
3828 SCH900776 dihydrochloride Potent, selective and orally bioavailable inhibitor of CHK1 Inquire
2531 SCR7 pyrazine DNA ligase IV mediated inhibitor of NHEJ €65.00
1956 Selisistat Potent and selective SIRT1 inhibitor €90.00
3737 Siremadlin Potent, selective, and orally bioavailable MDM2-p53 inhibitor €130.00
2453 SirReal 2 SIRT2 inhibitor with >1000 fold selectivity over SIRT1 and SIRT3 €95.00
2968 SIRT7 inhibitor 97491 Inhibitor of SIRT7 €135.00
2209 Sodium butyrate Noncompetitive inhibitor of multiple histone deacetylases (HDACs) €50.00
2437 SP 141 Specific MDM2 inhibitor with therapeutic effects in breast cancer models €120.00
4034 SR-4370 Synthetic inhibitor of histone deacetylase (HDAC) Inquire
1875 SRT 1720 tetrahydrochloride Activator of the sirtuin subtype SIRT1 €95.00
3605 TAK-931 CDC7 inhibitor €160.00
2502 Talazoparib Potent, selective, and orally available PARP1/2 inhibitor €90.00
2914 TAS-103 dihydrochloride Dual inhibitor of topoisomerase I (Topo 1) and topoisomerase II (Topo 2) €95.00
2326 Temozolomide DNA methylating agent; apoptosis inducer €50.00
2008 Tenovin 1 Activates p53 through inhibition of SIRT 1 and 2 €70.00
2249 Tenovin 6 Small water soluble p53 activator and SIRT inhibitor €105.00
2339 TH 1834 Tip60 histone acetyltransferase inhibitor €140.00
2271 TH 287 hydrochloride First-in-class MTH1 inhibitor €95.00
2996 TH 34 HDAC inhibitor (6, 8, 10 Selective) €120.00
2934 TH 5487 Potent and selective active-site OGG1 inhibitor €125.00
2272 TH 588 hydrochloride First-in-class MTH1 inhibitor €90.00
3285 TH1760 First-in-class, potent, selective and cell-active NUDT15 inhibitor €130.00
3402 THZ531 First-in-class, potent, selective, covalent CDK12/CDK13 inhibitor €130.00
2180 TMP 195 HDAC inhibitor (class IIA selective) €110.00

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