A5056418483- Cancer therapeutics and mechanisms
- Polyomavirus and related diseases
- Synthesis and Biological Evaluation
- Phenothiazines and Benzothiazines Synthesis and Activities
- Click Chemistry and Applications
- Synthesis of β-Lactam Compounds
- Renal Transplantation Outcomes and Treatments
- Protein Degradation and Inhibitors
- Bioactive Compounds and Antitumor Agents
- DNA Repair Mechanisms
- Genomics and Chromatin Dynamics
- Neutropenia and Cancer Infections
- Synthesis and biological activity
- Synthesis and Catalytic Reactions
National Institutes of Health
2024-2025
Center for Cancer Research
2024-2025
National Cancer Institute
2024-2025
Kyoto University
2020-2024
Application of copper-catalyzed azide–alkyne cycloaddition (CuAAC) “click” reactions assemble bivalent proteolysis-targeting chimeras (PROTACs) constituents targeting tyrosyl-DNA phosphodiesterase 1 (TDP1).
Topoisomerase III-beta (Top3b) reduces nucleic acid torsional stress and intertwining generated during RNA DNA metabolism while protecting the genome from pathological R-loops, which otherwise result in breakage instability. By studying Top3b knockout mice (Top3b-KO), we find that loss of accelerates development spontaneous lymphoid tumors arising spleens lymph nodes, organs with prominent expression. Aging Top3b-KO also display splenomegaly systemic immune alterations including neutrophilia...
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a potential target for cancer chemotherapy and radiotherapy. There are few reports on TDP1 inhibitors used in chemotherapy, but no report their use Herein, we designed synthesized series of titled analogues. Twelve analogues showed high inhibitory activity. Among them, 18 (IC50 = 6.9 μM) strong radiosensitization colorectal cells, could suppress tumor growth the HCT116 xenograft animal model combined with X-ray radiation, exhibited low acute toxicity...
Abstract Developing effective inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) has been challenging because shallow catalytic pocket and non-specific substrate binding interactions. Recently, we discovered a quinolone-binding hot spot in TDP1’s active site proximal to evolutionary conserved Y204 F259 residues that position DNA. Sulfur (VI) fluoride exchange (SuFEx) is biocompatible click chemistry reaction enables acylation protein residues, including tyrosine....
ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific after loss. Here, we report that controls the early transcriptional response estrogens. This depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins breaks. When TOP2-mediated ligation fails, facilitates DSB repair. After estrogen exposure,...
Abstract With its ligand estrogen, the estrogen receptor (ER) initiates a global transcriptional program, promoting cell growth. This process involves topoisomerase 2 (TOP2), key protein in resolving topological issues during transcription by cleaving DNA duplex, passing another duplex through break, and repairing break. Recent studies revealed involvement of various repair proteins TOP2-induced breaks, suggesting potential alternative pathways cases where TOP2 is halted after cleavage....
Androgens stimulate the proliferation of epithelial cells in prostate by activating topoisomerase 2 (TOP2) and regulating transcription target genes. TOP2 resolves entanglement genomic DNA transiently generating double-strand breaks (DSBs), where homodimers covalently bind to 5' DSB ends, called TOP2-DNA cleavage complexes (TOP2ccs). When fails rejoin TOP2ccs stalled TOP2ccs, tyrosyl phosphodiesterase-2 (TDP2) removes adducts from prior ligation DSBs nonhomologous end joining (NHEJ),...
Abstract Steroid hormones induce the transcription of target genes by activating nuclear receptors. Early transcriptional response to various stimuli, including hormones, involves active catalysis topoisomerase II (TOP2) at regulatory sequences. TOP2 untangles DNAs transiently generating double‐strand breaks (DSBs), where covalently binds DSB ends. When fails rejoin, called “abortive” catalysis, resulting DSBs are repaired tyrosyl‐DNA phosphodiesterase 2 (TDP2) and non‐homologous end‐joining...