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Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules. Protein degraders are an emerging drug modality; however, their properties lie beyond typical drug-like space. Here the authors report optimisation via structure-based exit vector and linker design towards the VHL-recruiting PROTAC ACBI2, an orally bioavailable and selective degrader of SMARCA2.

In 2014, the pyrronazols, a family of closely related natural products were isolated from a soil dwelling myxobacteria, Nannocystis pusilla strain Ari7. The family represent a novel structural class of secondary metabolites, containing a conjugated chlorinated pyrrole-oxazole unit. The total synthesis of pyrronazols A and A2, 20 and 21, has still to be accomplished and is of specific interest, not only for its unusual and interesting structure, but also to expand on the very limited biological profile. This could be probed further through the synthesis of structural analogues, thus requiring a synthetic strategy that tolerates rapid modifications to probe SAR. A synthetic strategy for the pyrronazol family must be flexible to allow for the synthesis of both isomers from a single privileged intermediate. Through our attempts towards the synthesis of the pyrronazol family this work details a highly syn-selective, substrate controlled vinylogous Mukaiyama aldol reaction (vMAR) which has been developed and optimised to install the required stereocentres on the pyranone ring. The (4S,5S) C₁-C₇ pyranone fragment has been utilised in the synthesis of two advanced intermediates, both a single reduction step away from pyrronazol A2, that have proved resistant to reduction. The alkene geometry, directing the synthesis towards pyrronazol A2, was set by an unprecedently selective Knoevenagel condensation between 5-chloro-2-formylpyrrole and amidoester partners. Our C₁-C₇ fragment has also been used in a convergent, modular synthesis of pyrronazol B, which afforded the natural product alongside an isomeric product.

A repeated measures design was used to evaluate a 12 month on-site counsellor internship programme aimed at training staff to support the recovery needs of people with co-occurring substance use and mental health disorders. Fifty-four interns completed measures of recovery knowledge, attitudes, confidence/competence, as well as identifying significant learning events. Statistically significant improvements were found in terms of attitudes and confidence/competence, and only one recovery knowledge factor, ‘roles of self-definition and peers in recovery’. Recovery knowledge at the end of the internship was positively associated with increases in interns’ confidence/competence but was not associated with changes in the interns’ attitudes. The mentoring, training/feedback and observational elements of the internship programme were highly valued by interns. Competency based learning events were most frequently identified as significant. Strategies to increase self-directed and interpersonally focused learning, and specific personal recovery knowledge in training are discussed.

Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue (1). However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand (2). Here we show that a single small molecule can be used to simultaneously and potently degrade 13 out of 17 of the most prevalent oncogenic KRAS alleles, including those not yet tractable by inhibitors. Compared with inhibition, degradation of oncogenic KRAS results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo. Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders. The most prevalent KRAS variants which drive tumour growth in a major share of cancer patients can be targeted with a single small molecule degrader.

The targeting of proteins to their correct subcellular location is essential for cells to function correctly. This requires a complex, tightly regulated membrane trafficking system that relies heavily on directed budding and fusion of intracellular transport vesicles. Fusion between the membranes of a vesicle and its target organelle involves the interaction between SNARE proteins and every SNARE-dependent fusion event that is known involves a member of the Syntaxin family. This study details the characterisation of the Drosophila Syntaxin family at the molecular level, and describes the role of these proteins in the Malpighian tubule, a model polarised epithelium.Analysis of the completed Drosophila genome revealed that the Drosophila Syntaxin family consists of ten members, each more closely related to its mammalian homologue than to each other. All ten members are expressed throughout Drosophila development and in all adult tissues studied, indicating the importance of this protein family and vesicle trafficking in general. Each Syntaxin is shown by immunocytochemistry to localise to a distinct intracellular domain and this distribution of Syntaxins is sufficient to argue for the existence of a regulated vesicle trafficking network within the cells of the Malpighian tubule. Two Syntaxins are localised to plasma membrane domains of the principal cell of the Malpighian tubule. Syntaxin 1A is found on the apical membrane, whilst Syntaxin4 is found specifically on basolateral domains. The function of these Syntaxins has been elucidated by the use of RNA-interference-mediated reverse genetics. Data from this project shows that Syntaxin 1A plays a role in the trafficking of components of the vacuolar-ATPase to the apical plasma membrane, whilst Syntaxin4 is involved in the activation of store-operated calcium channels in response to the neuropeptide-stimulated emptying of internal calcium stores. Furthermore, this study shows that the Malpighian tubules contribute to the innate immunity of Drosophila and that Syntaxin4 is essential for the tubules' ability to mount a response to challenge by Gram-negative bacteria. This project represents the first detailed characterisation of Syntaxin expression in a single cell type in higher eukaryotes. In doing so, it has shed light on the importance of polarised vesicle trafficking in the maintenance of a fully functional Malpighian tubule - a tissue critical to the viability of insects.

As humans continue to modify natural habitats in Africa, particularly outside of protected areas, the survival of many chimpanzee (Pan troglodytes) populations is dependant on their ability to adapt to human-dominated landscapes, and the willingness of local people to share their environment and resources with these large mammals. Unless hunted, chimpanzees may persist in anthropogenically-modified habitats including forest–farm mosaics, but competition and conflict can characterise their relationship with people. Conservation strategies are needed to facilitate successful coexistence. However, few studies have examined human–ape sympatry in detail. This thesis explores the ecological and behavioural adaptation of a previously unstudied chimpanzee community to an increasingly ‘agriculturalised’ landscape at Bulindi, Uganda. These chimpanzees live in exceptionally close proximity to farmers that exert unsustainable pressure on small unprotected forests. Research was conducted during 21 months between February 2006 and January 2008. Quantitative ecological methods were used to characterise the apes’ habitat and measure seasonal food availability. Indirect methods (e.g. faecal analysis and nest mapping) were employed to investigate chimpanzee diet and range use, supplemented by opportunistic behavioural observations. Riverine forests at Bulindi are rich in chimpanzee foods, but are rapidly being destroyed by people. Important foods in the apes’ diet include both wild and cultivated items; chimpanzees increased consumption of cultivars during the low forest fruiting season. Unique among studied populations in Uganda, Bulindi chimpanzees use tools to dig up subterranean bee nests for honey. Interviews were conducted to survey residents’ attitudes towards chimpanzees and forests. Chimpanzee behaviour is widely perceived by residents to have undergone recent negative changes, including increased crop-raiding and ranging into village areas, which correspond to major land-use changes (i.e. commercial logging and agricultural intensification). Further, adult males exhibit frequent human-directed aggression, apparently in response to harassment and intensifying competition with humans. Most residents fear chimpanzees. Because of poverty, insecure land tenure, inadequate law and policy enforcement, and corruption, local people currently have little incentive to maintain forest on their land. The study concludes that, under present conditions, chimpanzees will not survive at Bulindi or in similar unprotected forest–farm landscapes regionally without immediate, effective intervention. Recommendations for the conservation and management of chimpanzees in human-dominated landscapes are provided.