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.
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 | €90.00 | |
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 | |
2914 | TAS-103 dihydrochloride | Dual inhibitor of topoisomerase I (Topo 1) and topoisomerase II (Topo 2) | €95.00 | |
2502 | Talazoparib | Potent, selective, and orally available PARP1/2 inhibitor | €90.00 |