A5034187579- HER2/EGFR in Cancer Research
- DNA Repair Mechanisms
- Melanoma and MAPK Pathways
- 14-3-3 protein interactions
- Macrophage Migration Inhibitory Factor
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Protein Tyrosine Phosphatases
- Cancer therapeutics and mechanisms
- Metal complexes synthesis and properties
- RNA Research and Splicing
- Lung Cancer Treatments and Mutations
- Cytokine Signaling Pathways and Interactions
- Phytochemical compounds biological activities
- Genomics and Chromatin Dynamics
- PARP inhibition in cancer therapy
- RNA modifications and cancer
- Bioactive Compounds and Antitumor Agents
- Natural product bioactivities and synthesis
- DNA and Nucleic Acid Chemistry
- Cell Adhesion Molecules Research
- Cellular Mechanics and Interactions
- Phytochemistry and Bioactive Compounds
- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
Babraham Institute
2022
Cancer Research UK
2016-2021
Mission Therapeutics (United Kingdom)
2016
Cancer Research Horizons
2009
University of York
2004-2005
Newcastle University
2001-2005
To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function Polθ, including ART558. ART558 inhibits major Polθ-mediated process, Theta-Mediated End Joining, without targeting Non-Homologous Joining. In addition, elicits damage and synthetic lethality BRCA1- or BRCA2-mutant tumour cells enhances effects a PARP inhibitor. Genetic perturbation screening revealed that...
Structure−activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a morpholine substituent at this position was essential activity. Small libraries 6- and 7-alkoxy-substituted chromen-4-ones showed that number chromenones displayed improved Focused incorporating 6-, 7-, 8-aryl heteroaryl substituents were prepared. In these cases, 7-substitution disfavored, whereas...
A diverse range of chromen-2-one, chromen-4-one and pyrimidoisoquinolin-4-one derivatives was synthesized evaluated for inhibitory activity against the DNA repair enzyme DNA-dependent protein kinase (DNA-PK), with a view to elucidating structure−activity relationships potency selectivity. DNA-PK varied widely over series compounds (IC50 values ranged from 0.19 >10 μM), excellent being observed 7,8-benzochromen-4-one pyrimido[2,1-a]isoquinolin-4-one templates. By contrast, inhibitors based on...
Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated double strand break repair, has been proposed as an attractive target the treatment of BRCA deficient and other repair pathway defective cancers. As previously reported, we recently identified first selective small molecule Polθ in vitro probe, 22 (ART558), recapitulates phenotype loss, vivo 43 (ART812), efficacious a model PARP inhibitor resistant TNBC vivo. Here describe discovery, biochemical biophysical...
DNA polymerase theta (Polθ, encoded by the POLQ gene) is a repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but frequently overexpressed cancer cells and, therefore, represents an ideal target tumor-specific radiosensitization. In this study we evaluate whether targeting with novel small-molecule inhibitors feasible strategy to improve efficacy of radiotherapy.
Abstract DNA polymerase theta (Polθ) is a repair enzyme critical for microhomology mediated end joining (MMEJ). Loss or inhibition of Polθ has been shown to potentiate external beam radiation in tumour-specific manner1,2. However, the ability inhibitors open source not explored. This potential pertinent cancer therapy, as radioligand therapy (RLT), where radionuclide targeted tumour cells by linking peptides binding receptors, had recent clinical success, particular with 177Lu-PSMA-617...
The first total syntheses of the title fungal metabolites preussomerins F, K and L are described their structures confirmed thereby. were achieved following a versatile, unified, non-biomimetic approach, which is easily extendable to prepare other known novel members this family. Key steps include functionalisation 2-arylacetal anion, tandem one-pot Friedel-Crafts cyclisation-deprotection, regioselective substrate-directable hydrogenation reductive-opening epoxides.
As part of a program to develop small molecule inhibitor LIMK, series aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led low nanomolar LIMK1 LIMK2 that also inhibited the direct biomarker p-cofilin in cells invasion MDA MB-231-luc matrigel inverse assay.
Abstract ART0380 is a potent, selective and orally active inhibitor of ataxia telangiectasia Rad3-related (ATR) that has been developed for treatment cancer patients with DNA repair defects. Here we show preclinical data in range tumour xenograft models, both as monotherapy combination other DNA-damaging agents. As monotherapy, exhibits PD (γH2AX) effects efficacy comparable to the ATR BAY-1895344 but causing less toxicity gut. ATM highlighted synthetic lethal ATR, was also evaluated...
ABSTRACT DNA polymerase theta (Polθ) is a repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but frequently overexpressed cancer cells and, therefore, represents an ideal target tumor-specific radiosensitization. Here, we show that ART558 and ART899, two novel specific allosteric inhibitors of the domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, fibroblasts are...
Abstract To target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight, allosteric inhibitors of the polymerase function Theta (Polθ), including ART558. ART558 inhibits major Polθ-mediated process, Theta-Mediated End Joining (TMEJ), without targeting Non-Homologous Joining. Moreover, show that exposure to can elicit damage and synthetic lethality BRCA1- or BRCA2-mutant tumour cells enhances effects a PARP inhibitor. Genetic perturbation...
Abstract To target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function Polθ, including ART558. ART558 inhibits major Polθ-mediated process, Theta-Mediated End Joining (TMEJ), without targeting Non-Homologous Joining. Moreover, show that exposure to can elicit damage and synthetic lethality BRCA1- or BRCA2-mutant tumor cells enhances effects a PARP inhibitor. Genetic perturbation screening...
<div>AbstractPurpose:<p>DNA polymerase theta (Polθ) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but frequently overexpressed cancer cells and, therefore, represents an ideal target tumor-specific radiosensitization. In this study we evaluate whether targeting with novel small-molecule inhibitors feasible strategy to improve the efficacy of radiotherapy.</p>Experimental design:<p>We...
<p>Cell cycle-dependent effects of ART558 in combination with IR</p>
<p>Distribution of POLQ mRNA levels across cell lines from CCLE</p>
<p>Cell cycle-dependent effects of ART558 in combination with IR</p>
<p>Accompanies Figure 2 (ART558 treatment leads to increased residual IR-induced DNA damage foci)</p>
<p>Accompanies Figure 2 (ART558 treatment leads to increased residual IR-induced DNA damage foci)</p>