Human TDP1 cDNA Clone
- Known as:
- Human TDP1 complementary Desoxyribonucleic acid Clone
- Catalog number:
- DC01854
- Category:
- -
- Supplier:
- Abgen
- Gene target:
- Human TDP1 cDNA Clone
Related genes to: Human TDP1 cDNA Clone
- 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: Human TDP1 cDNA Clone
Related articles to: Human TDP1 cDNA Clone
- Resistance to targeted cancer therapies often arises from drug-tolerant cells, which survive treatment by entering a nonproliferative state. Over time, these cells can acquire mutations that contribute to cell reproliferation, but how nonproliferating drug-tolerant cells accumulate these mutations remains unclear. Here, we show that EGFR inhibition in -mutated lung cancer transiently down-regulates tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme that resolves abortive topoisomerase I cleavage complexes (TOP1ccs). In drug-tolerant cells, elevated reactive oxygen species promote TOP1cc trapping, while TDP1 down-regulation impairs their repair, driving TOP1cc accumulation, resistance mutation acquisition, and cell reproliferation. We further find that TDP1 expression is absent in ∼25% of -mutated lung cancers. In TDP1-deficient cells, combining EGFR inhibition with a sublethal concentration of topotecan, which further increases TOP1ccs, abolishes cell reproliferation. Together, these findings establish persistent TOP1cc accumulation as a driver of therapy-induced mutagenesis linking drug tolerance to adaptive resistance and reveal TDP1 loss as a targetable vulnerability in EGFR-mutated lung cancers. - Source: PubMed
Publication date: 2026/09/23
Geraud MathéaGence RemiCasanova AnneTaranchon-Clermont EstelleSalimbeni SimonaÖzsu NesibeVienne MainaDelahaye CéliaBorrull ElodieLusque AmélieMorisseau MathildeFilleron ThomasPagan DelphineTaha CamilleCristini AgneseMazières JulienCalvayrac OlivierFavre GillesPradines AnneSordet Olivier - Tyrosyl-DNA phosphodiesterase I (TDP1) repairs topoisomerase I (TOP1)-mediated DNA damage and is a promising anticancer target, particularly in combination with TOP1 inhibitors. However, the discovery of potent and drug-like TDP1 inhibitors remains challenging due to the limited structural diversity of known active compounds. Here, we developed an integrated computational framework combining machine learning (ML), deep learning (DL), and structure-based docking with experimental validation. A curated dataset of 2040 compounds (857 active, 1183 inactive) was assembled and analyzed by scaffold composition. A total of 40 binary classification models were constructed using six ML algorithms and a deep neural network (DNN), each paired with five molecular fingerprint representations, along with five graph neural network architectures (GCN, GAT, MPNN, AttentiveFP, and FPGNN). The SVM::RDKitDes model performed best (AUC = 0.89, 1 = 0.78, BA = 0.80), with robustness confirmed by Y-scrambling and randomized-split analyses, and SHAP analysis identified 20 key descriptors of TDP1 inhibition. The model was deployed as a web application (http://drugpred.top:5050) and standalone desktop applications (.exe) are available at https://github.com/zenghuang8006/TDP1-inhibitor-prediction. The validated model was applied to screen 201 231 compounds, followed by drug-likeness filtering and hierarchical docking, yielding 16 candidates. Biological evaluation identified compound AO65 as a potent TDP1 inhibitor (IC = 0.80 ± 0.02 µM), and quantum chemical calculations and docking elucidated its electronic properties and binding within the catalytic domain. This work demonstrates the value of integrating ML-driven prediction with structure-based approaches and identifies AO65 as a promising lead for further TDP1-focused investigation. - Source: PubMed
Publication date: 2026/08/12
Zeng HuangZhang ManyiQiu BoZhang ShengyuanLiu JiayaoLuo XiaodongWu LingfengXie HuasongZhai MingYang JiunlongYang HaoNie HuaWang Nan - 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