A5064968611- Synthesis and Catalytic Reactions
- Protein Degradation and Inhibitors
- Synthesis and Biological Evaluation
- Catalytic C–H Functionalization Methods
- Chemical Synthesis and Analysis
- Cyclopropane Reaction Mechanisms
- Coordination Chemistry and Organometallics
- Synthesis and biological activity
- Multiple Myeloma Research and Treatments
- Phenothiazines and Benzothiazines Synthesis and Activities
- PI3K/AKT/mTOR signaling in cancer
- Cancer therapeutics and mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Synthetic Organic Chemistry Methods
- Biochemical and Molecular Research
- Asymmetric Hydrogenation and Catalysis
- Cancer-related gene regulation
- Sulfur-Based Synthesis Techniques
- Organic and Inorganic Chemical Reactions
- Crystallization and Solubility Studies
- Peptidase Inhibition and Analysis
- X-ray Diffraction in Crystallography
- Epigenetics and DNA Methylation
- DNA Repair Mechanisms
- Chemokine receptors and signaling
AstraZeneca (United Kingdom)
2014-2023
AstraZeneca (Brazil)
2018
University of Warwick
2005
University of Southampton
2003-2004
ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series sulfonylmorpholinopyrimidines that show potent selective inhibition. Optimization from high quality screening hit within tight SAR space led compound 6 (AZ20) which inhibits immunoprecipitated HeLa nuclear extracts with IC50 5 nM mediated phosphorylation Chk1...
Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. is one "housekeeping" enzymes are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal chemically distinct tool compounds to those published allow us test hypothesis wide applicability treatment Here we present work led discovery three structurally different series inhibitors with excellent potency, selectivity, proven...
B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity based on mass spectrometry analyses following proteomic pull down. Importantly, proteolysis-targeting chimera (PROTAC) was also developed shown significantly degrade in number of diffuse large...
KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based design approach led the identification of 21, AZD4625, a clinical development candidate for treatment KRASG12C positive tumors. Highlights include quinazoline tethering strategy lock out bio-relevant binding conformation and optimization focused on reduction...
Inhibition of the protein–protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large (DLBCL) cancers profiling potent selective BCL6 inhibitors are critical to test this hypothesis. We identified pyrazolo[1,5-a]pyrimidine series binders from fragment screen parallel with virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming...
Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" has recently yielded covalent targeting small molecules that bind cysteine create allosteric pocket on GDP-bound RAS, locking it in inactive state. A weak inhibitor at this site was optimized through conformational of a piperazine-quinazoline motif linker modification. Subsequent introduction key methyl...
The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach led the identification 14, AZD4747, a clinical development candidate for treatment KRASG12C-positive tumors, including central nervous system (CNS) metastases. Building on earlier discovery C5-tethered quinazoline AZD4625, excision usually critical pyrimidine ring yielded weak...
ATAD2 is an epigenetic bromodomain-containing target which overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have described the literature, their cellular activity proved to be underwhelming. In this work, we describe identification of novel series by high throughput screening, confirmation bromodomain region site action, optimization campaign undertaken improve potency, selectivity, permeability initial hit. The...
Wide-ranging exploration of potential replacements for a quinoline-based inhibitor activation AKT kinase led to number alternative, novel scaffolds with potentially improved potency and physicochemical properties. Examples showed predictable DMPK properties, one such compound demonstrated pharmacodynamic knockdown phosphorylation downstream biomarkers in vivo inhibition tumor growth breast cancer xenograft model.
Amination of C-H bonds activated by ether oxygen atoms is facile with chloramine-T as nitrene source and copper(I) chloride in acetonitrile catalyst. For cyclic ethers the hemiaminal products are generally stable can be isolated pure. acyclic ethers, products, expected, fragment elimination alcohol to yield imines. When activation benzylic positions remote through a conjugated system, benzylamine derivatives isolated. Mechanistic studies consistent concerted insertion an electrophilic...
Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors catalytic subunit PRC2 enhancer zeste homologue (EZH2) being recently approved for treatment epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding EED have emerged as allosteric activity. In contrast orthosteric that target EZH2, small molecules bind retain their efficacy in EZH2 inhibitor-resistant cell lines. this...
Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that may be a resistance mechanism in cells undergoing stress response.
Abstract A palladium‐catalysed Buchwald–Hartwig amination for lenalidomide‐derived aryl bromides was optimised using high throughput experimentation (HTE). The substrate scope of the conditions evaluated a range alkyl‐ and aryl‐ amines functionalised bromides. methodology allows access to new cereblon‐based bifunctional proteolysis targeting chimeras with reduced step count improved yields.
The facile synthesis of both saturated and unsaturated tricyclic pyrrolo-pyridones starting from a single readily available, common monocyclic reagent has been developed. An intermolecular annulation via tandem Buchwald–Hartwig/Heck reaction led to the β-carbolinones. analogous semisaturated were prepared in good excellent yields by sequential Buchwald–Hartwig Fischer indole reactions. methods feature mild conditions functional group tolerance.
Isoquinolines activated with sulfamoyl chlorides were reacted indoles in a 3-component reaction to generate library of dihydroisoquinoline derivatives. Using differential protecting group strategy, products could be further derivatised. Synthesis isoquinoline starting materials using several different methods is also described.
Bicalutamide, a therapeutically important anti-androgen used in the treatment of hormone-sensitive cancers, may be synthesised from appropriate halohydrin or epoxide. We report here studies aimed at demonstrating unambiguously that preparation bicalutamide and its thioether analogue chlorohydrin under basic conditions proceeds via opening an intermediate epoxide by sulfinate thiolate nucleophile, analogous anionic sulfur nucleophiles react same S(N)2 pathway involving direct displacement...