Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a three-dimensional coculture model, AES-135 kills low-passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing

Reasons given for being unemployed and the job search progress

This paper examines whether the reasons given for being unemployed and for getting a previous job differentiate between those who later obtain jobs and those who remain unemployed. Initial interviews were carried out with 82 registered unemployed, 51 of whom participated in a follow-up one month later. Those who initially blamed their unemployment on a lack of jobs and who thought that success in the past was due to their own effort, were found to be more likely to obtain jobs. The dilemma of an active job search strategy which produces feelings of low well-being, but also a greater likelihood of obtaining work is discussed. Suggestions are given for ways of handling the conflict

Design and synthesis of small-molecule inhibitors targeting the SCFskp2 E3 ligase and the MDMX-p53 interaction for cancer therapy

PhD ThesisThe SKP1-Cullin1-F-box (SCF) E3 ligases promote the ubiquitination and proteasomemediated degradation of regulatory proteins. Subunits of the SCF complex have shown oncogenic activity, including the F-box protein S-phase Kinase-associated Protein 2 (SKP2). The SCFSKP2 E3 ligase targets several cell cycle negative regulators, e.g. p27, enabling replicative immortality. The only marketed drug that targets the ubiquitinproteasome system is Bortezomib (Velcade; Millenium Pharmaceuticals) (15), which is used to treat multiple myeloma, but has numerous side effects, as the result of targeting a proteasome involved in the regulation of multiple proteins. Targeting an F-box protein is an attractive solution because the F-box protein defines E3 ligase selectivity and each E3 ligase regulates fewer proteins. To date, no small molecule targeting an F-box protein has entered clinical trials. A recently reported compound, (((3-(2,2- dimethyltetrahydro-2H-pyran-4-yl)-4-phenylbutyl)amino)methyl)-N,N-dimethylaniline (16a), has shown evidence to suggest it inhibits the SCFSKP2 ligase. The synthesis of 16a (diastereoisomeric mixture) was completed at Newcastle University and growth inhibitory activity was confirmed in HeLa cells using a sulforhodamine B assay. Both enantiomers of N,N-dimethyl-4-(((4-phenyl-3-(tetrahydro-2H-pyran-4- yl)butyl)amino)methyl)aniline (68a) were synthesised, in one of the first documented enantioselective syntheses of a molecule of this chemotype, and demonstrated similar growth inhibitory activity in HeLa cells to each other and to the racemate, suggesting the compounds have a non-specific mechanism of action. ID HeLa GI50 (μM) 68a 27 ± 4 (S)-68a 33 ± 4 (R)-68a 29 ± 2 vi Murine double minute 2 (MDM2) and its structurally related homologue MDMX (MDM4) negatively regulate the protein level and transcriptional activity of the tumour suppressor p53. Overexpression of MDM2 and MDMX has been observed in multiple human cancers and is associated with cell immortality. Co-crystallisation of the p53-MDM2 and p53-MDMX complexes showed that three p53 residues (F19, W23 and L26) are critical to the formation of these dimers and smallmolecule inhibitors function by competitively blocking the p53-binding sites on MDM2 or MDMX. Several small-molecule MDM2 inhibitors have entered clinical trials; however, no small-molecule MDMX inhibitor has reached the same stage. A recently discovered series of 2,4-disubstituted thiazoles have shown modest potency against MDM2 and MDMX. In silico modelling suggested the compounds interacted with the p53-binding domains in both proteins and extensive SAR studies around 4-(2-((4- fluorobenzyl)amino)thiazol-4-yl)benzene-1,2-diol (59a) were conducted. This series was extended to include benzenoid and pyrrole-based compounds, including 2’-(4- chlorophenoxy)-3’-((4-fluorophenyl)amino)-[1,1’-biphenyl]-4-ol (138c) and 2-(4- chlorobenzyl)-1-(4-chlorophenyl)-5-(4-fluorophenyl)-1H-pyrrole-3-carboxylic acid (220c). All three chemotypes demonstrated low micromolar activity against MDMX and MDM2 by ELISA. ID MDMX IC50 (μM) MDM2 IC50 (μM) 59a 24.7 12.1 138c 19.0 23.2 220c 14.6 11.2 Current efforts are focussing on potentiating MDMX potency in each of the above chemotypes and trialling various co-crystallisation conditions so as to understand the molecules’ binding mechanism and guide rational drug design.Cancer Research U

Reasons given for being unemployed and the job search progress

This paper examines whether the reasons given for being unemployed and for getting a previous job differentiate between those who later obtain jobs and those who remain unemployed. Initial interviews were carried out with 82 registered unemployed, 51 of whom participated in a follow-up one month later. Those who initially blamed their unemployment on a lack of jobs and who thought that success in the past was due to their own effort, were found to be more likely to obtain jobs. The dilemma of an active job search strategy which produces feelings of low well-being, but also a greater likelihood of obtaining work is discussed. Suggestions are given for ways of handling the conflict

Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as standalone or in combination with targeted drugs.Peer reviewe

A Sequential Guessing Game for Studying Problem Solving

A binary guessing game was used to study non-verbal problem solving. Results suggested that inappropriate expectancies interfere with performance on this task. A distinction between simple and complex learning was made and a concept learning paradigm presented for these findings. </jats:p