Ask about this productRelated genes to: TDP1 antibody
- Gene:
- TDP1 NIH gene
- Name:
- tyrosyl-DNA phosphodiesterase 1
- Previous symbol:
- -
- Synonyms:
- FLJ11090, SCAN1
- Chromosome:
- 14q32.11
- Locus Type:
- gene with protein product
- Date approved:
- 2002-07-13
- Date modifiied:
- 2008-08-11
Related products to: TDP1 antibody
Related articles to: TDP1 antibody
- Herein, we report a solvent-controlled, operationally convenient and highly efficient rhodium(II)-catalysed protocol enabling hydrodehalogenation and phenanthridinone skeleton construction from 2-halobenzamide. This methodology facilitates the hydrodehalogenation of diverse 2-halobenzamides using isopropanol, providing quantitative yields without further purification. Furthermore, this strategy allows the direct and efficient conversion of 2‑halobenzamides into phenanthridinones by aprotic solvent. Additionally, a series of phenanthridinone derivatives were synthesised and evaluated for their inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase IB (TOP1), as well as their cytotoxicity. Compound showed potent TDP1 inhibitory activity (IC = 4.5 ± 0.4 μM) and synergistic effect with topotecan and radiosensitising effect in HCT116 cells by stabilising cellular TDP1 cleavage complexes (TDP1cc). Compound exhibited strong TOP1 inhibition (+++) and induced the formation of cellular TOP1 cleavage complexes (TOP1cc) and DNA damage, and consequently triggered apoptosis. studies indicated that exhibits antitumor efficacy in HCT116 xenograft model. - Source: PubMed
Publication date: 2026/07/28
Hu De-XuanQin ChaoGao XiangTang LingZheng YaxinYin Rui - Tyrosyl-DNA phosphodiesterase 1 (TDP1) represents a compelling pharmacological target for the development of agents designed to circumvent tumor resistance to topoisomerase 1 (TOP1) inhibitors, a major class of clinically relevant antineoplastic drugs. This paper describes the design and synthesis of novel hybrid TDP1 inhibitors combining coumarin and monoterpene moieties via rigid isoxazole and 1,2,3-triazole heterocyclic linkers. The synthesis was accomplished via [3 + 2] cycloaddition of nitrile oxides to alkynes and copper-catalyzed click chemistry. Biological tests have demonstrated the crucial role of linker nature in the activity of the compounds. Isoxazole-linked conjugates showed strong inhibitory effects on TDP1, with IC values in the submicromolar to low micromolar range (0.8-3.2 μM). Overall, these values slightly surpassed those of the triazole-linked analogues, whose IC values ranged from 1.1 to 23.3 μM. At noncytotoxic doses, compounds and enhanced the sensitivity of human cervical cancer (HeLa) cells to the antitumor agent topotecan, a TOP1 inhibitor, thereby supporting the promise of this structural class as components of combination chemotherapy. - Source: PubMed
Publication date: 2026/07/19
Tsypyshev DmitriyKhomenko TatyanaKornienko TatyanaZakharenko AlexandraKomarova NinaKrasnov VyacheslavSoldatova NatalyaPostnikov PavelSari SuatVolcho KonstantinLavrik OlgaSalakhutdinov Nariman - [This corrects the article DOI: 10.17912/micropub.biology.000693.]. - Source: PubMed
Publication date: 2026/06/03
- The NF-κB signaling pathway is a key driver of inflammation and can be activated by many genotoxic stresses. Yet, the mechanisms by which different types of DNA damage trigger NF-κB remain poorly understood. In this study, we find that NF-κB activation by topoisomerase 1 (TOP1) inhibition is strongly increased when cells are treated in combination with PARP inhibitors. Mechanistically, we demonstrate that TOP1 inhibition activates ATM-mediated NF-κB signaling through two distinct pathways: a replication-dependent pathway triggered by replication fork collapse and a replication-independent pathway revealed upon PARP1 inhibition. We further show that PARP1 enzymatic activity is not required to suppress NF-κB signaling after TOP1 inhibition during the replication-independent pathway. Instead, PARP inhibitors trap PARP1 at DNA lesions, thereby blocking repair and promoting ATM-dependent NF-κB signaling, mimicking the cell response to TDP1 depletion. These findings reveal an unexpected role for PARP1 as an NF-κB activator when trapped at DNA lesions induced by TOP1 inhibition, providing a therapeutic opportunity to use PARP inhibitors to enhance inflammatory responses and potentially improve the efficacy of TOP1-targeted cancer therapies. - Source: PubMed
Bournique ElodieSanchez AmbrocioHa KimYan Katrina MManjunath LavanyaSantiago GisselleOrtega PedroBuisson Rémi - DNA topoisomerases manage the supercoiled structure of the genomic DNA through breaking and rejoining DNA strands, which is a key step in many cellular processes. DNA topoisomerase I (TOPI) forms TOPI-DNA cleavage complex (TOPIcc) formation of a transient covalent bond between TOPI and the DNA single strand. Inhibition of TOPI enzymatic activity is a successful approach for treating multiple types of cancer. Tyrosyl-DNA phosphodiesterase 1 (TDP1) helps release of TOPIccs catalysis of TOPI-DNA phosphodiester bond hydrolysis. TDP1 is therefore functionally connected with activity of TOPI. Poly [ADP-ribose] polymerase 1 (PARP1) physically interacts with TDP1 to make TDP1 PARylated and enhances TDP1 recruitment to DNA damage sites, thus playing a functional role in TOPIcc repair. If unrepaired, TOPIcc can lead to single strand breaks, which cause cell death. Slowing down TDP1 activity can increase the efficacy of existing TOPI inhibitors and improve their clinical utility. Repair of TOPIccs can be negatively impacted by blocking the physical interactions between TDP1 and PARP1. Therefore, blocking the TDP1-PARP1 complex formations has the potential to enhance the antitumor activity of existing FDA approved TOP1 inhibitors and reduce their side effects. Towards this aim, we identified binding sites that are crucial for the TDP1-PARP1 complex formation using 700 ns long molecular dynamics (MD) simulations. We identified specific interactions between D115(TDP1) and K940 or K943 (PARP1) as well as R137(TDP1) and E883(PARP1) that might be important for the TDP1-PARP1 complex formation. We validated the complex formation between purified recombinant TDP1 and PARP1 proteins using surface plasmon resonance (SPR). We also used SPR to confirm that peptides corresponding to contact points between TDP1 and PARP1 prevent complex formation. Our findings lead the path for creating novel inhibitors that can prevent TDP1 binding to PARP1 and consequently improve the clinical efficacy of the current TOP1 inhibitors for cancer treatment. - Source: PubMed
Publication date: 2026/06/17
Wang SophiaÜren AykutTiwari Purushottam B