A5051512925- Microtubule and mitosis dynamics
- Phosphodiesterase function and regulation
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Heat shock proteins research
- Cancer Genomics and Diagnostics
- Protein Structure and Dynamics
- Chemical Synthesis and Analysis
- Epigenetics and DNA Methylation
- Protease and Inhibitor Mechanisms
- Enzyme Structure and Function
- PI3K/AKT/mTOR signaling in cancer
- CAR-T cell therapy research
- Computational Drug Discovery Methods
- Cancer Treatment and Pharmacology
- Cancer-related Molecular Pathways
- Protein Tyrosine Phosphatases
- Click Chemistry and Applications
- Cancer therapeutics and mechanisms
- RNA modifications and cancer
- Peptidase Inhibition and Analysis
- Carbohydrate Chemistry and Synthesis
- Pancreatic function and diabetes
- Melanoma and MAPK Pathways
- Endoplasmic Reticulum Stress and Disease
Institute of Cancer Research
2015-2024
Cancer Research UK
2011-2022
Romax Technology (United Kingdom)
2003
Birkbeck, University of London
2001-2003
University of Groningen
1994-1998
The HSF1-mediated stress response pathway is steadily gaining momentum as a critical source of targets for cancer therapy. Key mediators this include molecular chaperones such heat shock protein (HSP) 90. There has been considerable progress in targeting HSP90 and the preclinical efficacy signs early clinical activity inhibitors have provided proof-of-concept group proteins. HSP70 family are also key HSF-1-stress multiple additional roles folding, trafficking degradation, well regulating...
We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind Fe(II) in active site. Substitution from C4 pyrazole moiety allows access peptide substrate binding site; incorporation conformationally constrained 4-phenylpiperidine linker gives such as 54j...
The screening of fragments is an alternative approach to high-throughput for the identification leads therapeutic targets. Fragment hits have been discovered using X-ray crystallographic protein crystals serine protease enzyme thrombin. fragment library was designed avoid any well-precedented, strongly basic functionality. Screening included a novel ligand (3), which binds exclusively S2−S4 pocket, in addition smaller bind S1 pocket. structure these protein−ligand complexes are presented. A...
The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and aberrantly overexpressed in many human cancers. one top 25 genes tumors with chromosomal instability aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon for their survival, making it target significant interest oncology. We report discovery optimization potent selective inhibitors based on 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design cellular...
Deregulation of the transcriptional repressor BCL6 enables tumorigenesis germinal center B-cells, and hence has been proposed as a therapeutic target for treatment diffuse large B-cell lymphoma (DLBCL). Herein we report discovery series benzimidazolone inhibitors protein–protein interaction between its co-repressors. A subset these were found to cause rapid degradation BCL6, optimization pharmacokinetic properties led...
We report herein the first systematic exploration of inhibitors mitotic kinase Nek2. Starting from HTS hit aminopyrazine 2, compounds with improved activity were identified using structure-based design. Our structural biology investigations reveal two notable observations. First, 2 and related bind to an unusual, inactive conformation which best our knowledge has not been reported for other types inhibitors. Second, a phenylalanine residue at center ATP pocket strongly affects ability...
The members of the NSD subfamily lysine methyl transferases are compelling oncology targets due to recent characterization gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable small molecule inhibition. Here, we present initial efforts identify inhibitors MMSET (aka NSD2 or WHSC1) using solution phase crystal structural methods. On basis 2D NMR experiments comparing NSD1 mobility, designed an construct with five point...
Abstract The stress‐inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors cells difficult owing to competition the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized could be overcome using a cysteine‐targeted irreversible inhibitor. Using rational design, we adapted validated 8‐ N ‐benzyladenosine ligand for...
Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using unbiased phenotypic screen to detect inhibitors HSF1 stress pathway. The probe is orally bioavailable displays efficacy in human ovarian carcinoma xenograft...
TRF1 is a subunit of the shelterin complex that binds to and protects linear ends chromosomes known as telomeres. Both genetic deletion chemical inhibition have been shown block growth lung carcinoma, glioblastoma, renal cell carcinoma in mice without affecting mouse survival or tissue function, making potential therapeutic target cancer 1-3 . Here, we report discovery series fragment hits bind at interface between TRFH domain (TRF1 ) peptide TIN2 (TIN2 TBM ), an interaction essential for...
Crystallins are long-lived proteins packed inside eye lens fiber cells that essential in maintaining the transparency and refractive power of lens. Members two-domain betagamma-crystallin family assemble into an array oligomer sizes, forming intricate higher-order networks cell. Here we describe 1.4 angstroms resolution crystal structure a truncated version human betaB1 resembles vivo age-related truncation. The shows unlike its close homolog, betaB2-crystallin, homodimer is not domain...
Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series potent CHK1-selective isoquinolines demonstrates how fragment-growing scaffold morphing strategies arising from structure-based understanding inhibitor binding can be combined successfully progress fragment-derived hit matter compounds activity in vivo. challenges improving selectivity,...
The Nek family of serine/threonine kinases regulates centrosome and cilia function; in addition, several its members are potential targets for drug discovery. Nek2 is dimeric, cell cycle regulated functions the separation centrosomes at G2/M. Here, we report crystal structures wild-type human kinase domain bound to ADP 1.55-A resolution T175A mutant apo form as well that a non-hydrolyzable ATP analog. These show regions structure around nucleotide-binding site can adopt different but...
We describe herein the structure−activity relationship (SAR) and cocrystal structures of a series Nek2 inhibitors derived from published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal nonlinear SAR for our show that compounds in this bind to DFG-out conformation without extending into enlarged back pocket commonly found conformation. These observations were further investigated, structure-based design led (R)-1 with more than hundred-fold selectivity against Plk1.
HSP70 is a molecular chaperone and key component of the heat-shock response. Because its proposed importance in oncology, this protein has become popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived inhibitors potentially bind to with novel mechanism action, stabilization by desolvation an intramolecular salt-bridge induces conformational change protein, leading high affinity ligands. We also demonstrate through...
Abstract BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. treatment alone induces significant sensitization to death, particularly in proliferative triple-negative breast cancer (TNBC) cell lines with compromised activity. synergizes paclitaxel induce gross chromosomal segregation defects caused by MPS1 inhibitor–mediated abrogation the mitotic delay induced treatment. In vivo pharmacodynamic experiments,...
To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent Val18. With no opportunities for strong polar interactions, focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration different sized rings, identified conformationally restricted core which optimally filled available space, leading potent BCL6 inhibitors. Through X-ray structure-guided...
Abstract Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and rapidly translating into clinical agents. However, fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed issue in design CRL4 CRBN recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used generate PROTACs have well described intrinsic monovalent profiles by recruitment neo‐substrates,...
High hit rates from initial ligand-observed NMR screening can make it challenging to prioritize which hits follow up, especially in cases where there are no available crystal structures of these bound the target proteins or other strategies provide affinity ranking. Here, we report a reproducible, accurate, and versatile quantitative assay, determine Kd values fragments range low μM mM using transverse relaxation rate R2 as observable parameter. In this study, examined theory proposed...
We describe and apply a scaffold-focused virtual screen based upon scaffold trees to the mitotic kinase TTK (MPS1). Using level 1 of tree, we perform both 2D 3D similarity searches between query library derived from 2 million compound library; 98 compounds 27 unique top-ranked scaffolds are selected for biochemical screening. show that this prospectively identifies eight confirmed active structurally differentiated compound. In comparison, 100 were screening using whole molecule resulting in...