Synthesis, the science of making molecules, is central to human wellbeing through its ability to produce new molecules for use as medicines and materials. Every new drug, whether an antibiotic or a cancer treatment, is based on a molecular structure designed and built using the techniques of synthesis. Synthesis is a complex activity, in which bonds between atoms are formed in a carefully choreographed way, and training to a doctoral level is needed to produce scientists with this expertise. Our proposed CDT is tailored towards training the highly creative, technologically skilled scientists essential to the pharmaceutical, biotech, agrochemical and materials sectors, and to many related areas of science which depend on novel molecules. Irrespective of the ingenuity of the synthetic chemist, synthesis is often the limiting step in the development of a new product or the advance of new molecular science. This hurdle has been overcome in some areas by automation (e.g. peptides and DNA), but the operational complexity of a typical synthetic route in, say, medicinal chemistry has hampered the wider use of the technology. Recent developments in the fields of automation, machine learning (ML), virtual reality (VR) and artificial intelligence (AI) now make possible a fundamental change in the way molecules are designed and made, and we propose in this CDT to engineer a revolution in the way that newly trained researchers approach synthetic chemistry, creating a new generation of pioneering innovators. Making use of Bristol's extensive array of automated synthetic equipment, flow reactors, peptide synthesisers, and ML Retrosynthesis Tool, students will learn and appreciate this cutting-edge technology-driven program, its potential and its limitations. Bristol has outstanding facilities, equipment and expertise to deliver this training. At its core will be a state-of-the-art research experience in our world-leading research groups, which will form the majority of the 4-year CDT training period. For the 8 months prior to choosing their project, students with complete a unique, multifaceted Technology & Automation Training Experience (TATE). They will gain hands-on experience in advanced techniques in synthesis, automation, modelling and virtual reality. In conjunction with our Dynamic Laboratory Manual (DLM), the students will also expand their experience and confidence with interactive, virtual versions of essential experimental techniques, using simulations, videos, tutorials and quizzes to allow them to learn from mistakes quickly, effectively and safely before entering the lab. In parallel, they will develop their teamworking, leadership and thinking skills through brainstorming and problemsolving sessions, some of them led by our industrial partners. Brainstorming involves the students generating ideas on outline proposals which they then present to the project leaders in a lively and engaging interactive feedback session, which invariably sees new and student-driven ideas emerge. By allowing students to become fully engaged with the projects and staff, brainstorming ensures that students take ownership of a PhD proposal from the start and develop early on a creative and collaborative atmosphere towards problem solving. TATE also provides a formal assessment mechanism, allow the students to make a fully informed choice of PhD project, and engages them in the use of the key innovative techniques of automation, machine learning and virtual reality that they will build on during their projects. We will integrate into our CDT direct interaction and training from entrepreneurs who themselves have taken scientific ideas from the lab into the market. By combining our expertise in synthesis training with new training platforms in automation, ML/AI/VR and entrepreneurship this new CDT will produce graduates better able to navigate the fast-changing chemical landscape.

Melanoma is an increasingly devastating cancer of the skin, whose occurrence is on the rise. It can be treated surgically but long term survival tends to be poor. Often, once detected, it has already metastasised (spread to other parts of the body) and surgical intervention merely removes the original cancer, with the more aggressive form inoperable or intractable (unresponsive) to chemo- or radio- therapies). Thereafter, fatality is inevitable. Fortunately, there are a number of new therapies available for melanoma including "vemurafenib", which is a synthetic molecule acting on a specific mutation (change in a key protein vital for cancer progression, called BRAFV600E (amino acid residue number 600 of the BRAF protein has changed from a valine to a glutamic acid, drastically altering the cancerous nature of the protein)). However, around 50% of melanomas do not carry this particular mutation and therapy is ineffective in these cases. Ipilimumab or pembrolizumab (Keytruda) are newly introduced immunotherapy-based antibody drugs, which cause cells to attack the melanoma by activating the immune system. Many of these drugs are dramatically more effective in combination with others since they can attack the cancer in complementary ways, preventing problematic resistance to the treatments. Indeed, recent clinical trials on the immunotherapy approach have shown very encouraging results with > 2 years survival noted for a number of patients, although side effects in over half of the patients halted their treatment (http://www.bbc.co.uk/news/health-36043882). Hence, despite huge strides in melanoma treatments, the search for new therapies is still vital particularly for melanomas that are not harbouring BRAF-mutations. We have recently discovered a range of molecules that target parts of proteins called bromodomains (BRDs) that are crucial in gene transcription in cancer. One particular BRD, called PHIP, is highly expressed in many melanomas, particularly aggressive types and it has been shown (by De Semir et al., who is a collaborator on this application) that stopping PHIP production biologically, slows down melanoma progression in cells (in vitro), as well as in mice (in vivo). Our recent study has shown, for the first time, how small molecules can inhibit and bind to PHIP(2), one of the forms of PHIP, at the atomic level, by x-ray crystallography. The next stage is to take our original PHIP(2) acting molecules and improve their biological activity and selectivity over other BRDs (there are over 60 of these) in order to be able to use smaller doses, to lower toxicity, side effects and cost. This will act as a proof of principle to show that PHIP(2) inhibition by drug-like molecules is a vital new armoury in our fight against skin cancer. Although a study of this magnitude is unlikely to yield a drug, since this tends to cost a billion or so pounds and take over 12 years, it is expected to contribute to a better understanding of the role of PHIP(2) in melanoma and to a new line of chemical reactions towards biologically active molecules, which may act on either PHIP(2) or on other BRDs. PHIP(2) is an example of an atypical BRD (there are 13 of these vs 48 typical BRDs). Little is known about their inhibition so this study will also have ramifications in atypical BRD inhibition and lead to others studying other atypical BRDs. It will also add to the very important area of epigenetics, a study of inheritable changes of the genome not related to DNA sequence changes, which is an area of science that is en vogue, spanning different branches of science such as environmental factors including diet-related disease and addiction (Brazil, R. Chemistry World, 2016, 34-39).