A5073664926- HER2/EGFR in Cancer Research
- Melanoma and MAPK Pathways
- DNA and Nucleic Acid Chemistry
- Computational Drug Discovery Methods
- Cancer therapeutics and mechanisms
- Advanced biosensing and bioanalysis techniques
- Protein Tyrosine Phosphatases
- Lung Cancer Treatments and Mutations
- DNA Repair Mechanisms
- Click Chemistry and Applications
- 14-3-3 protein interactions
- Macrophage Migration Inhibitory Factor
- RNA Interference and Gene Delivery
- PI3K/AKT/mTOR signaling in cancer
- Metal complexes synthesis and properties
- Cytokine Signaling Pathways and Interactions
- RNA Research and Splicing
- Synthesis and biological activity
- Genomics and Chromatin Dynamics
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- RNA modifications and cancer
- Quinazolinone synthesis and applications
- PARP inhibition in cancer therapy
- Biochemical and Molecular Research
Babraham Institute
2022
Charles River Laboratories (United Kingdom)
2015-2022
Charles River Laboratories (Netherlands)
2014
Harlow College
2014
University of Nottingham
2001-2008
Georgia State University
2008
The Open University
2008
Inserm
2008
Centre National de la Recherche Scientifique
2008
University of Arizona
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...
A novel pentacyclic acridine, 3,11-difluoro-6,8,13-trimethyl-8<i>H</i>-quino[4,3,2-kl]acridinium methosulfate (RHPS4), has been identified as a potent inhibitor of telomerase in the cell-free telomeric repeat amplification protocol (TRAP). Modeling and biophysical studies suggest that RHPS4 inhibits through stabilization four-stranded G-quadruplex structures formed by single-stranded DNA. In contrast to interactive inhibitors described previously, inhibited at submicromolar levels (50%...
Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In course of discovery novel benzoxepin PI3K inhibitors, we observed a strong dependency in vivo antitumor activity on free-drug exposure. By lowering intrinsic clearance, derived set imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth tumors mouse xenograft model at low dose levels. One these compounds,...
Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kα have received substantial attention for their potential use in cancer therapy. Despite particular attraction targeting PI3Kα, achieving selectivity inhibition this has proved challenging. Herein we report discovery inhibitors that over other isoforms and all kinases tested. In GDC-0032 (3, taselisib), previously minimized PI3Kβ relative to insoforms. Subsequently, extended our efforts identify PI3Kα-specific using...
Small molecule inhibitors that target the phosphatidylinositol 3-kinase (PI3K) signaling pathway have received significant interest for treatment of cancers. The class I isoform PI3Kα is most commonly associated with solid tumors via gene amplification or activating mutations. However, demonstrating both PI3K and mutant specificity remained elusive. Herein, we describe optimization characterization a series benzoxazepin-oxazolidinone ATP-competitive which also induce selective degradation...
For biologically interfaced sensing applications, nanostructured porous silicon (PSi) is a very promising candidate, since mammalian cells can be cultured directly onto it. The development of cell culture systems for PSi–cell interface described, together with the more "nature-identical" simulated plasma (SP). Figure shows an SEM image crystallites that have formed on nanoporous Si exposed to SP 25 days.
Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency (<1 μM) in the TRAP assay. 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (12d, RHPS4, NSC 714187) has a higher selectivity for triplex and quadruplex DNA structures than 3,6,8,11,13-pentamethyl analogue (12c, RHPS3, 714186) low overall growth-inhibitory activity NCI 60 cell panel (mean GI50 13.18 μM); addition, profile of 12d...
The growth-inhibitory activities of an extensive series quaternized quino[4,3,2-kl]acridinium salts against tumor cell lines in vitro have been measured and their biological properties interpreted the light differential binding to different DNA isoforms. Selectivity for quadruplex stabilization by compounds were explored through array methods: UV absorption fluorescence emission spectroscopy, surface plasmon resonance, competition dialysis. Quadruplex interaction was further characterized...
Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions exon 19, increase EGFR-driven cell proliferation and survival are correlated with impressive responses to EGFR inhibitors erlotinib gefitinib in nonsmall lung cancer patients. Approximately 60% of acquired resistance these agents is driven by a single secondary mutation specifically substitution gatekeeper residue threonine-790 methionine (T790M). Due dose-limiting toxicities...
Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation the gatekeeper residue, means that clinical responses only last for 8–14 months. Addressing this unmet medical need requires agents can target both most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750)...
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.
Guided by 24 drug–DNA NOEs, the complex formed between RHPS4 (a novel fluorinated polycyclic methylacridinium salt with potent telomerase activity) and d(TTAGGGT)4 has been modeled using MD simulations drug molecules intercalated at ApG GpT steps. A low-energy structure for 2:1 a partial positive charge on acridine 13-N atom (which acts as pseudo potassium ion) positioned above center of G-tetrad (see picture).
Telomeric integrity is required to maintain the replicative ability of cancer cells and a target for G-quadruplex–stabilizing drug 3,11-difluoro-6,8,13-trimethyl-8<i>H</i>-quino[4,3,2-<i>kl</i>]acridinium methosulfate (RHPS4). We report senescent-like growth arrest in MCF-7 breast cells, within 14 17 days, reduction telomere length (from 5.2 kilobases (kb) 4.7 4.3 kb after days treatment at 0.5 1 μM, respectively). These effects occurred noncytotoxic concentrations (doses < μM over 14-day...
Using structure-based design, two novel series of highly potent biaryl amine mitogen-activated protein kinase (MEK) inhibitors have been discovered. These contain an H-bond acceptor, in a shifted position compared with previously disclosed compounds, and adjacent donor, resulting bidentate interaction the Ser212 residue MEK1. The most compound identified, 1 (G-894), is orally active vivo pharmacodynamic tumor xenograft models.
The rapid advancement of a series noncovalent inhibitors T790M mutants EGFR is discussed. optimization pyridone 1, nonselective high-throughput screening hit, to potent molecules with high levels selectivity over wtEGFR and the broader kinome described herein.
Inhibitors targeting the activating mutants of epidermal growth factor receptor (EGFR) have found success in treatment EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) inhibitor binding site has been linked to acquired resistance against those first generation therapeutics. Herein, we describe lead optimization a series reversible, pan-mutant (L858R, del746-750, T790M/L858R, and T790M/del746-750) inhibitors. By use noncovalent double (T790M/L858R selective...
Palladium(0)-mediated Suzuki−Miyaura and Heck transformations have been exploited to provide examples of 8-methylquino[4,3,2-kl]acridines 8,13-dimethylquino[4,3,2-kl]acridinium iodides bearing bulky saturated (3-acetoxy)propyl or (E)-3-(morpholin-4-yl)-3-oxopropenyl substituents variously in the 3-, 6-, 10-positions pentacyclic nucleus. The pharmacological/pharmaceutical properties four compounds (4, RHPS4), (5, IH383), (6, RHPS16), (17, RHPS19) were measured assess their clinical potential...
In an effort to identify potent and isoform selective inhibitors of PI3Kδ, GNE-293 (34) was identified. Inhibitor 2 found induce micronuclei formation in both the MNT HCA vitro assays. Compounds testing negative for genotoxicity were successfully identified through modifications 2-benzimidazole substituent methylene moiety disrupt planarity. A variety heteroatom linkers explored examine their effect on potency selectivity by restricting torsional angles favor ligand interactions with PI3Kδ's...
A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound 3, an αPI3K inhibitor, we utilized structure-based drug design and computational analysis dihedral torsion angles to optimize for isoform potency selectivity. Further medicinal chemistry optimization the series led identification 24, a highly potent PI3Kδ.
The antileukemic xanthone psorospermin is a topoisomerase II−dependent DNA alkylator in advanced preclinical development. Efforts have been made to further understand the structural requirements of its mechanism action through synthesis ring-constrained analogues, based on skeleton bisfuranoxanthone natural products. Molecules were designed that contain bisfuran and portions naturally occurring psorofebrins, molecular modeling was used assess their alkylating potential refine structures. A...