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
3735 ZZW-115 trihydrochloride Potent NUPR1 inhibitor €140.00
2675 YMU1 Selective inhibitor of human thymidylate kinase (hTMPK) €110.00
2268 XL 413 hydrochloride Potent, selective and orally bioavailable CDC7 inhibitor €120.00
1527 XAV939 Tankyrase (TNKS) inhibitor €80.00
2385 WZ 4003 Specific dual inhibitor of NUAK1 (ARK5) and NUAK2 (SNARK) €80.00
3995 WT-161 Potent,selective,and bioavailable HDAC6 inhibitor Inquire
3114 Vorinostat HDAC inhibitor €45.00
2888 Veliparib dihydrochloride PARP inhibitor €95.00
1593 Veliparib PARP inhibitor €40.00
2452 VE 822 Selective ATR inhibitor that decreases survival of pancreatic cancer cells €110.00
1893 VE 821 Inhibitor of the DNA damage response kinase ATR €80.00
2369 UPF 1069 PARP-2 inhibitor with >26 fold selectivity over PARP1 €75.00
2418 UNC0379 Substrate competitive inhibitor of the H4K20 HMTase SETD8 €125.00
2518 UF 010 Class I selective HDAC inhibitor that inhibits cancer cell proliferation €60.00
2893 Tucidinostat Orally bioavailable HDAC inhibitor (1, 2, 3, 10 Selective) €95.00
2004 Tubastatin A hydrochloride Potent and selective HDAC6 inhibitor €95.00
3691 Tubacin HDAC6 inhibitor Inquire
2100 Trovafloxacin mesylate Inhibitor of bacterial DNA gyrase and Topo IV €110.00
2180 TMP 195 HDAC inhibitor (class IIA selective) €110.00
3402 THZ531 First-in-class, potent, selective, covalent CDK12/CDK13 inhibitor €130.00
3285 TH1760 First-in-class, potent, selective and cell-active NUDT15 inhibitor €130.00
2272 TH 588 hydrochloride First-in-class MTH1 inhibitor €90.00
2934 TH 5487 Potent and selective active-site OGG1 inhibitor €125.00
2996 TH 34 HDAC inhibitor (6, 8, 10 Selective) €120.00
2271 TH 287 hydrochloride First-in-class MTH1 inhibitor €95.00
2339 TH 1834 Tip60 histone acetyltransferase inhibitor €140.00
2249 Tenovin 6 Small water soluble p53 activator and SIRT inhibitor €105.00
2008 Tenovin 1 Activates p53 through inhibition of SIRT 1 and 2 €70.00
2326 Temozolomide DNA methylating agent; apoptosis inducer €50.00
2914 TAS-103 dihydrochloride Dual inhibitor of topoisomerase I (Topo 1) and topoisomerase II (Topo 2) €95.00

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