A5047982869- Cancer therapeutics and mechanisms
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- PARP inhibition in cancer therapy
- Acute Myeloid Leukemia Research
- Immune Response and Inflammation
- Biochemical and Molecular Research
- Protein Degradation and Inhibitors
- Chemical Synthesis and Analysis
- Synthesis of β-Lactam Compounds
- DNA Repair Mechanisms
- Fluorine in Organic Chemistry
- Chromatin Remodeling and Cancer
- Coordination Chemistry and Organometallics
- Mechanisms of cancer metastasis
- Synthesis and Biological Evaluation
- Cancer, Hypoxia, and Metabolism
- Genomics and Chromatin Dynamics
- Receptor Mechanisms and Signaling
- Synthesis and Reactivity of Heterocycles
- Cell death mechanisms and regulation
- Synthesis of heterocyclic compounds
- Endoplasmic Reticulum Stress and Disease
- Melanoma and MAPK Pathways
- Cancer Mechanisms and Therapy
Cancer Research UK Manchester Institute
2012-2022
Loughborough University
2022
University of Manchester
2012-2019
Pfizer (United Kingdom)
2011
University of Liverpool
2008
Highlights•Inhibitors of LSD1 target both scaffolding and enzymatic functions the protein•GFI1/CoREST complex is targeted for disruption release from chromatin•GFI1/CoREST required leukemia cell differentiation•Loss enhancer-bound GFI1/LSD1 activates nearby myeloid differentiation genesSummaryPharmacologic inhibition promotes blast in acute (AML) with MLL translocations. The assumption has been that induced through blockade LSD1's histone demethylase activity. However, we observed rapid,...
The enzyme poly(ADP-ribose) glycohydrolase (PARG) performs a critical role in the repair of DNA single strand breaks (SSBs). However, detailed understanding its mechanism action has been hampered by lack credible, cell-active chemical probes. Herein, we demonstrate inhibition PARG with small molecule, leading to (PAR) chain persistence intact cells. Moreover, describe two advanced, and chemically distinct, tool compounds convincing on-target pharmacology selectivity. Using one these...
Two series of aminothiazoles have been developed as reversible inhibitors lysine specific demethylase 1 (LSD1) through the expansion a hit derived from high concentration biochemical fragment based screen 2466 compounds. The potency initial was increased 32-fold synthesis, with one compounds showing clear structure–activity relationships and inhibitory activities in range 7 to 187 μM assay. This also showed selectivity against related FAD-dependent enzyme mono-amine oxidase A (MAO-A)....
Novel derivatives of the steroid DHEA 1, a known uncompetitive inhibitor G6PD, were designed, synthesized, and tested for their ability to inhibit this dehydrogenase enzyme. Several compounds with approximately 10-fold improved potency in an enzyme assay identified, activity translated efficacy cellular assay. The SAR inhibition G6PD has been substantially developed; 3β-alcohol can be replaced 3β-H-bond donors such as sulfamide, sulfonamide, urea, carbamate. Improved was achieved by...
The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In clinical setting, it hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological is proposed as a novel approach overcome intrinsic or acquired topo II-targeted therapy. Following high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified...
Chronic inflammation is a hallmark of many cancers, yet the pathogenic mechanisms that distinguish cancer-associated from benign persistent are still mainly unclear. Here, we report protein kinase ERK5 controls expression specific subset inflammatory mediators in mouse epidermis, which triggers recruitment cells needed to support skin carcinogenesis. Accordingly, inactivation keratinocytes prevents inflammation-driven tumorigenesis this model. In addition, found anti-ERK5 therapy cooperates...
The Target Of Rapamycin TOR kinase regulates cell growth and division. only inhibits a subset of activities. Here we show that in contrast to the mild impact rapamycin on division, blocking catalytic site with Torin1 inhibitor completely arrests without death S.pombe. A mutation Tor2 TORC1 glycine residue (G2040D) lies adjacent key Torin interacting tryptophan provides resistance, confirming Torin1's specificity for TOR. Using this advanced mitotic onset before inducing arrest. In inhibition...
A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification a novel series inhibitors. Elucidation bound ligand crystal structure showed that inhibitors exhibited binding mode in previously identified allosteric site (R132H). This information guided optimization yielding submicromolar enzyme with promising cellular activity. Encouragingly, one compound from this was found induce myeloid differentiation...
DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays pivotal role regulation mechanisms; however, lack potent drug-like inhibitors use cellular vivo models has limited investigation its potential as novel target. Using crystal structure human PARG complex with weakly active cytotoxic anthraquinone 8a, quinazolinedione sulfonamides have been...
The development and implementation of a scalable process for the manufacture Toll-like receptor (TLR7) agonist PF-4171455 (1) is described. Initial routes used to synthesise 1 in milligram quantities were unsuitable large-scale synthesis provide bulk material. As part transfer between Medicinal Chemistry Research-API, collaboration provided fit purpose route kilo-scale 1. Key aspects included (i) safe practical key nitropyridone intermediate 7 over four steps, (ii) sequential regioselective...
Structure-based drug discovery (SBDD) largely relies on structural information from X-ray crystallography because traditional NMR structure calculation methods are too time consuming to be aligned with typical timelines. The recently developed molecular replacement (NMR2) method dramatically reduces the needed generate ligand–protein complex structures using published (apo or holo) of target protein and treating all observed NOEs as ambiguous restraints, bypassing laborious process obtaining...
Fluorination of metabolic hotspots in a molecule is common medicinal chemistry strategy to improve vivo half-life and exposure and, generally, this offers significant benefits. Here, we report the application series poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting unexpected toxicity which was attributed single-atom modification.
Abstract Aim: With the decreasing costs of genomics technologies, ever more data is being put into public domain. Scientific papers only highlight a fraction information in data, consequently further mining can answer drug discovery relevant questions and identify new targets. In this work we developed bioinformatics pipeline, based on collateral vulnerability hypothesis, to integrate several sources novel targets form basis project. Methods: Genomic from TCGA was integrated with phenotypic...