Unusual Undergraduate Training in Medicinal Chemistry in

May 23, 2017 - However, despite many and varied initiatives in drug discovery, based on recent new drug applications, there is little evidence across ...
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Unusual Undergraduate Training in Medicinal Chemistry in Collaboration between Academia and Industry Miniperspective Thomas McInally† and Simon J. F. Macdonald*,‡ †

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, University of Nottingham, Triumph Road, Nottingham NG7 2TU, United Kingdom ‡ Fibrosis & Lung Injury Discovery Performance Unit, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom S Supporting Information *

ABSTRACT: Globalization has driven new paradigms for drug discovery and development. Activities previously carried out predominantly in the United States, Europe, and Japan are now carried out globally. This has caused considerable change in large pharma including how medicinal chemists are trained. Described here is the training of chemistry undergraduates in medicinal chemistry (as practiced in industry) in two modules developed in collaboration between the University of Nottingham (UoN) and GlaxoSmithKline (GSK). The students complete several design−synthesize−test iterations on medicinal chemistry projects where they carry out the design and synthesis, and GSK tests the compounds. Considerable emphasis is placed on standard design properties used within industry. The modules are popular with the students and usually oversubscribed. An unexpected benefit has been the opportunities that have emerged with research and commercial potential. Graduate and postgraduate training of medicinal chemists at GSK is also briefly described.

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INTRODUCTION

Alongside this demand, the drug discovery and development model is undergoing profound change particularly in Europe and the United States. It has been estimated that the number of medicinal chemists employed in the pharmaceutical industry in the United Kingdom decreased by about a third since 2007.4 Alongside this, between 2009 and 2014 in the U.S. alone the pharmaceutical industry announced more than 156 000 job cuts.5 Many scientific positions in big pharma and biotech have moved to outsourcers located particularly in the East (for example, in India and in China), and many other roles have moved from big pharma to small biotech companies and, in particular in the U.K. and other areas in Europe, into contract research organizations (CROs). Activities across the whole drug discovery spectrum previously regarded as sacrosanct and so confidential that they could only be carried out in-house are now routinely outsourced, and there is little indication at present when this transfer will reach maturity. The consequences of these changes are profound at every level, but our focus here is on the impact on medicinal chemistry training. Several recent articles articulate the issue. Dave Allen, Senior Vice President of Respiratory Therapy Area and head of respiratory drug discovery in GlaxoSmithKline (GSK) and chief chemist recently provided his reply to the question “Where will we get the next generation of medicinal chemists?”4 In an

A recent article from Rafferty described medicinal chemistry training as being in big trouble1 for a variety of reasons. We agree. But we are doing something about it, and in telling our story here we hope to inspire readers to develop their own initiatives. In sharing it, we are not so much describing a blueprint as providing an illustration of what can be done. The aging demographic of populations in the West and in Japan (inter alia), the proliferation of chronic diseases, and the rising consumer wealth are all predicted to be long-term drivers for healthcare spending. In growth markets, the demand for medicines and the middle classes (who can afford them) are both expanding while the value of the global biotech market rises annually.2,3 Despite the rise in the numbers of new biologics launched (mostly for cancer and rare diseases), on average they cost considerably more than small molecules (approximately $15K for a biologic compared with approximately $700 for a conventional therapy per patient per year), and so there is still enormous scope for safe and efficacious small molecule drugs. However, despite many and varied initiatives in drug discovery, based on recent new drug applications, there is little evidence across the industry of any surge in pharmaceutical productivity and the average cost to launch a new drug between 2005 and 2010 was $4.2 billion, 50% more than the previous 5-year period (although other estimates are somewhat lower).3 © 2017 American Chemical Society

Received: February 6, 2017 Published: May 23, 2017 7958

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online analysis, Bruce Booth suggests “the seeds are being sown for a major talent crisis in our industry”.6 He goes on to indicate that the traditional apprenticeship and training of medicinal chemists in drug discovery (regarded as taking at least 5 years and usually more than 10) occur in big pharma who are cutting back on internal research including medicinal chemistry and switching to outsourcing models. In this context therefore, Rafferty’s recently published perspective entitled “No Denying It: Medicinal Chemistry Training Is in Big Trouble” elegantly describes the challenges the industry faces.1 These articles are written from a European and U.S. perspective. Like other major industries, drug discovery and development institutions that historically operated predominantly in these regions (and also in Japan) are now embracing globalization with all the accompanying benefits and challenges. So while at an individual, company, and regional level these changes are often painful requiring new paradigms, new roles and new skills for scientists (including closely related disciplines to medicinal chemistry such as chemical biology, inter alia), they also represent a huge opportunity for regions and countries where previously only modest amounts of drug discovery took place. Nonetheless, establishing how medicinal chemistry will continue in Europe and the U.S. and how the next generation of scientists based in those regions will be developed is important. The global winds of change make it likely that the answers will look quite different from those in the past, and the standard career paths for medicinal chemists of the past 50 years are unlikely to remain as well trodden. As will be discussed elsewhere, we envisage the traditional role of the medicinal chemist in big pharma at least to continue its transition into a new role we term a “drug discoverer” and that training our medicinal chemists as we did in the past (laboratory based and with a long apprenticeship) will continue to dwindle. Moving from the laboratory to the office distances the medicinal chemist from the synthetic chemistry; helpful synthetic insights and a detailed appreciation of the chemistry can be missed leading to inefficiency and tensions with the bench or CRO chemist. Nonetheless the aims of the training described here are essentially to introduce the students to the standard concepts used by the medicinal chemist rather than to train “drug discoverers” or “molecular designers”. A consequence of pharma downsizing is that any company loyalty felt by staff is often eroded. Many biotechs will only have transient existence before they are either taken over by big pharma or closed through lack of funding or failure to discover assets. The new medicinal chemist will thus have to be nimble at jumping between roles and companies which is challenging because drug discovery is a long process and perseverance with a program is required for several years to identify the clinical candidate. Frequent job changes reduce the chance to make a substantial contribution to the science. Michael Rafferty’s article was therefore timely and articulated our own experience. We echo almost every point made. However, we have started to address this by responding to a vision provided by Sir Andrew Witty, a recent chief executive officer of GSK and Chancellor of the University of Nottingham (UoN) to deliver “industry ready graduates”. For over 5 years, this major initiative between GSK and UoN in the U.K. has developed a novel approach to drug discovery training experienced to date by over 150 students. Furthermore, quite unexpectedly, benefits and opportunities have emerged that perhaps exemplify the principle of achieving goals indirectly or obliquely.7

Perspective

INDUSTRIALISTS TEACHING MEDICINAL CHEMISTRY TO UNDERGRADUATES GSK sponsors two undergraduate modules in the School of Chemistry at the UoN: one for third years8 and another for fourth years9 (comprehensive details are provided in refs 8 and 9). The aims of both are the same: to teach the principles of medicinal chemistry as practiced in drug discovery in industry in both the classroom and the laboratory. We differentiate between the aims of industrial medicinal chemistry and academic medicinal chemistry. The usual aims of the former drive toward patents, compounds that can be tested clinically, and ultimately new medicines. The latter may also have these aims but other aims (and frequently higher priority) are the generation of new knowledge and the publication of high impact papers. There is clearly merit in both activities, but our focus in these modules is the former. It is of course completely unrealistic to expect inexperienced undergraduates to optimize leads and to deliver new clinical candidates, but this is nonetheless the goal. The control that this goal exerts over the journey (or teaching experience) is crucial. In so doing, the students come to learn the molecular disciplines required in industry. Among many other factors, they learn that drug discovery is a balance of properties with constant trade-offs, that compounds must be druglike, that irritating functionality from a synthetic standpoint has to be accommodated because it contributes to the pharmacological profile, that control of lipophilicity is critical, that some aqueous solubility transforms the development pathway, that pure, dry samples accurately weighed and registered into a database may be boring but are important, and that potency is just one of many considerations. Thus, we address head-on many of the issues and concerns raised by Rafferty. We recognized at the outset that the overarching aim was and is to teach students science, so any emerging intellectual property and any novel ideas generated by GSK scientists within these modules are owned exclusively by the UoN. But as we will describe briefly later, by having discipline and rigor in pursuing one goal, we have obliquely also achieved others of real value. The third year undergraduate project (usually involving about 20 students per year split into teams) is on the discovery of pi3kδ inhibitors for asthma.8 There are six taught workshops introducing them to medicinal chemistry, drug discovery, compound design, and the basic pathology of asthma alongside basic target validation for pi3kδ inhibitors. In the next four workshops the students become actively involved in the detail of the project with each team mentored by a practising GSK medicinal chemist. Their goal is to design compounds with increased potency but, most importantly, at the same time to control lipophilicity, consider metabolic stability, and maintain and/or improve aqueous solubility. They design a virtual array (focused library), and then based on those data (generated and supplied by GSK), they design a second iteration of compounds which they will synthesize themselves in the lab. These compounds are tested by GSK and the data returned to the students. They then prepare a report that summarizes these data together with the experimental procedures, some analysis, and discussion. The aim is for the students to experience two iterations of the analysis−design−synthesize−test cycle which is probably one of the major learning points in medicinal chemistry. Due to the limited curriculum time and the inexperience of the students, the third year module is quite 7959

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with one to two students per 2 m fume cupboard. The laboratory is equipped with standard glassware, and students have access to shared infrared, 1H NMR, high performance liquid chromatography/mass spectrometry, and high resolution mass spectrometry facilities. The fourth year students are expected to work a minimum of 18 h per week on the project which can be a combination of laboratory work and private study, although in reality, most students spend more than 25 h per week in the laboratory. The students receive formal graduate-level research chemistry safety training but undergraduates work in the laboratory under the supervision of McInally or a staff colleague at all times (nominally 9 a.m. to 5 p.m. Monday to Friday). No weekend working is allowed. All experiments must be preceded by a mandatory risk assessment of reagents and substrates which are signed off by McInally or a staff member. There is no specific policy to restrict the chemistry carried out by the undergraduates, but a certain degree of pragmatism is used. For example, n-butyllithium would be acceptable but tertbutyllithium would be avoided. The project is worth 50% of the credits for the final year, and the final year is worth 40% of the M.Sci. degree.

heavily choreographed (with detailed plans and timings particularly for the practical lab sessions); if it were not, it is unlikely the students would complete the work in the time available. Early in the project, the students are asked to work in teams and are provided with an introduction to team skills using Belbin profiles.10 This usually comes as a surprise to them as the vast majority of their academic life up to this point has predominantly been based on their own individual contributions. In contrast, the students taking the fourth year module (with about 10 students per cohort) optimize αvβ6 integrin inhibitors as a potential therapy for idiopathic pulmonary fibrosis (IPF) and are engaged (more or less) in full time research projects. In the first week of term/semester, the students are given a crash course in the basics of medicinal chemistry, introductions to integrins, IPF, and the science (target validation) supporting the hypothesis that modulation of αvβ6 may have therapeutic benefit for treating IPF and the aims of their projects together with the profile of the lead compounds.11 They design their targets (with help from the authors) which they then synthesize with the compounds being tested at GSK, and this sets the pattern for the rest of the year. Each annual cohort builds on the results generated by previous cohorts so there is slow but steady progress toward molecules having the desired profile. Preliminary results have recently been published.12 Considerable emphasis is placed on high quality target design. Selection of functionality designed to interact with residues in the active site is heavily influenced by those found in oral integrin antagonists that have been tested clinically. Other design considerations include the potential for permeability and metabolic stability, the absence of groups that have potential for toxicity alongside careful control of physicochemical properties. In other words, the design process reflects those used by the medicinal chemist in industry. The fourth year students usually complete two analysis− design−synthesize−test iterations in several series. Of course it is unrealistic to expect the students to complete complex multistep syntheses in the first term/semester, although more challenging syntheses are usually undertaken in the second term/semester. There is some choreography of the projects by the authors but considerably less than with the third year project as there is more time and the students are a little more experienced. Some midstage intermediates are usually supplied by GSK to ensure the students experience several lead optimization cycles and generate sufficient data to explore SAR which are included in their final year reports.13 However, there is considerable scope for the students to steer the project as they prefer: some have explored synthetic routes to enantiomerically pure compounds, others data analysis and quantitative structure−activity relationship techniques with yet another developing an assay for screening mixtures of compounds using a mass spectrometry based equilibrium dialysis.14 In each case the students have worked with UoN academics or GSK employees to ensure their research is high quality. Over the past 5 years or so, the UoN has therefore accumulated a library of over 300 druglike integrin inhibitors in several series with accompanying data from more than 10 biological and physicochemical assays generated by professional scientists at GSK. In response to questions from one of the reviewers, the third and fourth year students use the same teaching laboratory that is shared for 4 weeks at the start of the second term/semester

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TRANSFERABILITY: KEY POINTS By this point, some reasonable questions are “But what does it cost?” and “How do I run a version of this at my institution where a similar level of investment from a large pharma is not available?” These are fair questions. Indeed the two most important catalytic factors in running the modules have been (i) the provision of budget by GSK (and the UoN) and (ii) the acceptance that students will work on projects that are live within GSK. To avoid confusion around intellectual property, the chemical series optimized by the students are derived from the literature and are distinct from GSK’s own novel lead optimization series. Regarding budget, the modules have been (and are) funded centrally within GSK by the office of the Chief Executive Officer (CEO) (previously Andrew Witty and currently Emma Walmsley) and cover the salary of a Teaching Fellow and modest amounts for reagents, glassware, and basic equipment. Laboratory overhead facility costs are borne by the UoN. Substantial in-kind contributions are also made by GSK scientists in testing the students’ compounds multiple times in numerous assays, on GSK employees’ time (one of the authors is seconded to UoN for 20% of his time), and covering travel to and from the UoN. As can be imagined, securing resource within GSK for an external project is facilitated by its sponsorship from the CEO! A substantial budget is not, however, a necessity. The third year module in the School of Chemistry is very popular and generally heavily oversubscribed. As a consequence, a related but separate module developed by GSK Teaching Fellows Jonathan Fray and Andrew Nortcliffe has been made available to those students who are otherwise unable to enroll in the GSK sponsored program. This second module uses much of the same teaching material but is otherwise not supported by GSK and does not feature any laboratory based practical work. Another example also comes from the UoN. Under the inspired leadership of Dr. Michael Stocks, Associate Professor in the School of Pharmacy, a version of the third year module was developed for Pharmacy Masters students (M.Sci.) which embraced synthetic chemistry, computational chemistry, and biology. The material was adjusted to reflect the different skills and knowledge of pharmacy students. GSK supported this in 7960

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quotes Sir James Black the discoverer of β blockers and antiulcerants: “I used to tell my colleagues (in ICI17) that if they wanted profits, there were many easier routes than drug research. How wrong could I have been! I call it the principle of obliquity: goals are often best achieved without intending them.” In other words, by working toward one goal (here teaching undergraduates medicinal chemistry as practised in industry with all the accompanying constraints that follow), others are achieved that are beneficial. With each fourth year cohort generating approximately 50 compounds per year, the UoN now has a library of over 300 integrin modulators with accompanying data. These are valuable resources that we are seeking to exploit further. On the basis of these and the new intellectual property that they represent, we have written several substantial grant proposals, initiated collaborations across several schools in the university and elsewhere, held extended discussions about forming a spinout company, are in discussions about a licensing opportunity, and started three Ph.D. studentships. Some of these have been funded by UoN, some by GSK, and others jointly. On the basis of the work of the undergraduates, two peer reviewed publications12,14 have already emerged and there are plenty of new data for several more. There are enough interesting and commercially exploitable opportunities that funding for a Research Fellow at the UoN has been secured. Alongside this, GSK scientists have been able to develop a wide range of new skills including teaching and operating more effectively in the university environment. The personal development for one of the authors (S.J.F.M.) in being actively involved in the design and operationalization of undergraduate modules has been surprising and probably difficult to achieve without this type of enterprise.

running several workshops, the provision of intermediates, and in testing the compounds made by the students. A final example comes from Queen Mary University of London where Dr. Lisa Rooney also ran a version of the module where support from GSK was limited to supply of some intermediates. In each case the material was modified to suit the needs, situation, and interest of the academic department. It is striking that in each case, the organizing academic had previously been employed as a medicinal chemistry in industry; perhaps it is easier to see the appeal, value, and purpose of the modules with this background. When we started out, setting up teaching/research projects at the UoN that ran parallel to live GSK programs felt acutely uncomfortable. It ran contrary to the usual confidentiality of big pharma, although it was and is aligned with the GSK paradigm of a collaborative approach to drug discovery.15 In retrospect, however, it has provided significant advantages. Foremost is that the pi3 and αvβ6 assays were already being run for GSK programs, so the challenge of securing resource to run assays which would only be used for teaching purposes at a university was absent. In addition the background material that underpins the teaching was immediately to hand and familiar and thus easily converted into slide-packs; the reader almost certainly knows the time required to generate substantial amounts of new teaching material. In particular for the fourth year projects, being familiar with the αvβ6 literature, being deeply embedded in a GSK drug discovery project on αvβ6 integrin inhibitors, and having academic contacts in the field have all allowed GSK staff to make a much greater impact with relatively little extra commitment of time. So how can modules like these be set up? • Clearly, a high trust relationship between the institutions is required.16 In this regard, ex-industrial medicinal chemists now in academia probably have the contacts and the background to sell the advantages of the module content to their academic peers while also being able to contact former industrial colleagues for help (who may also reap unexpected benefits; vide infra). • Operating a teaching or research project in the same area as a live project in industry overcomes issues relating to the cost and resource of running assays solely to support academic teaching. • A significant commitment of time/resource both at the university and also within in the biotech/pharma is required particularly during the initial setup phase. • There needs to be considerable flexibility on both sides to accommodate constraints. For the industrialist, examples are realizing what is reasonable to expect an undergraduate to know and accomplish, what chemicals are best avoided for safety reasons, and the inflexibility of academic timetables and examination requirements. For the academic, an example is appreciating the rigidity of industrial processes for submitting and registering compounds for test where there are many rules!

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WHAT DO THE STUDENTS THINK?

The modules are popular with the undergraduates and are usually oversubscribed. Common themes in feedback18 from the students include an appreciation for the following: • The applied nature of the science: the line of sight to something useful (i.e., a medicine) although distant is particularly appealing to many in contrast to goals of pure science which are predominantly “new” knowledge. • The emphasis on team working. Students appreciate the support network fellow team members provide. Several students have commented how working in teams in the lab has transformed their experience from “I used to hate labs, but now I love them”. • Setting them up for their careers as medicinal chemists. We routinely ask the students for their candid feedback (see also the Supporting Information), and for example, Pippa O. a graduate from the 2016 cohort wrote

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OBLIQUITY: ACHIEVING DRUG DISCOVERY GOALS INDIRECTLY One of the most remarkable aspects of GSK’s involvement in teaching medicinal chemistry to undergraduates is that it has obliquely led to a series of unexpected benefits which were not the original goal. In his book “Obliquity”, John Kay7 illustrates the concept that goals are often best achieved indirectly. He 7961

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“[The 4th year module] was incredibly useful for me when settling into my role at Charles River as I am regularly involved in team meetings to discuss compound design and biological data to decide and rationalise future work plans. This was very similar to how the Masters project was run, making settling into working life a lot smoother, which was appreciated by both myself and my mentors. Being taught by industrial experts allowed me to gain a new perspective on organic synthesis. With an “end goal” in mind, I was required to work efficiently in a given time frame, a must-have skill for a medicinal chemist. I don’t think I missed out from not being supervised by an academic as in the end I still learnt the same synthetic and analytical techniques as I would have done in an academic project. I think I gained a lot more from the project as it taught me all the necessary skills to be able to apply my abilities as a chemist directly to industry, definitely giving me an advantage over other graduates when it came to job-searching. As well as being thoroughly enjoyable, the exposure to a drug development project made me stand out from the crowd and helped me into the pharma industry straight after graduation.” This and other feedback8,9,18 all indicate that the modules accurately reflect science in a professional (as much as educational) environment. The students are taught and begin to learn professional behaviors (teamwork, Belbin profiles, meeting skills, phone etiquette, and so on) which they feel are helpful to them both in securing employment and once they embark on their careers. We should stress however that our overall aim is not so much as to “convert” students to careers in applied chemistry in industry as to allow them to make more informed career choices. So have we succeeded? Many have certainly been excited by the prospect of carrying out research (Figure 1), and 41% have enrolled in Ph.D. programs (and thus have yet to decide on a career), with 25% going onto careers in the pharma industry as medicinal chemists (17%) or in other roles (8%).

Unfortunately comparative data with chemistry graduates who did not take the modules cannot be reported. It is worth commenting here that our impression is that the majority of graduates and postgraduates in the U.K. (and possibly other areas in Europe also) now see CROs rather than big pharma as the more likely place to find initial employment. In this regard the profile of new recruits sought by CROs and big pharma may be different reflecting the roles the chemists will play in the medium to long term. On the basis of conversations with U.K. based CROs, their preference is still primarily for Ph.D. synthetic chemists (and sometimes no medicinal chemistry questions are asked in the interview process). Their role is lab based in synthetic chemistry with medicinal chemistry learnt “on the job”.19 In contrast, at GSK there is a greater balance between the numbers of graduates and postgraduates recruited and more attention is paid to assessing medicinal chemistry understanding. For example, a recently qualified Ph.D. recruit at GSK might, within 2 years, be expected to supervise Ph.D. students, run small groups or teams, and lead a medicinal chemistry series. While they are still expected to make a synthetic contribution, this is increasingly regarded as lower impact and much of their “synthetic work” is now carried out by others (temporary staff or outsourced). The career trajectory is that the new recruits arrive as chemists but rapidly become drug discovers where a detailed knowledge of medicinal chemistry is just one of the required skills. So across the various drug discovery organizations that recruit chemists, there is a continuum covering the preferred experience of new recruits (predominantly synthetic to a mixture of synthetic and medicinal chemistry), the work they will be asked to do within the first 3−5 years (synthesis or a variety of drug discovery tasks of which synthesis is just one), and the roles they are ultimately being trained for and being asked to fill.

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OTHER TRAINING INITIATIVES

We have focused here predominantly on our experiences of training the next generation of chemists at the UoN. This is just one of several initiatives underway at GSK.4 In a creative use of Ph.D. studentships, the Fibrosis & Lung injury Discovery Performance Unit (small units charged with discovering new candidates for particular diseases) at GSK funded four Ph.D. studentships with Professor Joseph Harrity at the University of Sheffield and another four studentships (two per year for two years) with Drs. Allan Watson and Craig Jamieson at the University of Strathclyde on two drug discovery projects for IPF in an attempt to achieve critical mass. In both cases, a fundamental component of the academic group selection was the already very strong connections between them and GSK. Although ultimately the projects were embedded in the academic groups, they were initially selected by medicinal chemists at GSK (rather than the academics) who then had a significant influence on the strategic direction of the science. They worked very closely with the academics and the students with teleconferences every 2 weeks for progress updates. As detailed elsewhere,4 GSK runs a program whereby GSK graduate employees work toward a Ph.D. with the University of Strathclyde based on their current internal drug discovery project. This was later broadened to include an “Industrial Ph.D.” program whereby students from the same university are based at GSK for almost the entire period of their funding and work on projects directly aligned with GSK programs. There are numerous students enrolled in both programs.

Figure 1. 7962

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Perspective

CONCLUSION We share our experiences here to inspire and to encourage others to engage with finding new approaches to train the next generation of medicinal chemists for industrial drug discovery. We do not suggest what we have done as a blueprint but more an example of how to train students given the resources and opportunities we have had. A major advantage to the university and the associated company is the opportunities that are likely to emerge paying rich dividends in unexpected ways. With suitable levels of organization and guidance, it has been possible to carry out interesting and productive applied research with undergraduates. As perhaps is typical, the constraints of working with inexperienced undergraduates whose synthetic and medicinal chemical skills are limited have proved to be stimuli to innovation and new ideas.20 In the GSK−UoN collaboration, we have frequent opportunities to observe the students in marking their reports, presentations, and oral examinations where a large percent of the questions relate to medicinal chemistry. In addition we have many informal interactions with the students and ask for and receive their candid verbal and written feedback. Our assessment is that while they are just at the start of their training as medicinal chemists, they develop a relatively sophisticated awareness of some of the standard drug discovery properties which were so noticeably absent in the analyses carried out by Rafferty.1

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Medicinal Chemistry in the Fibrosis and Lung Injury Discovery Performance Unit in the Respiratory Therapeutic Area at GSK in Stevenage, U.K., and is a Visiting Professor at the University of Nottingham.

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ACKNOWLEDGMENTS We particularly recognize Dr. Jonathan Fray (the first GSK Teaching Fellow at the UoN) who was instrumental in setting up, refining, and delivering these modules and particularly the third year module. His insight, wisdom, pragmatism, and high standards together with his natural aptitude for teaching were exceptional. We are also deeply grateful to James Rowedder at GSK who, as the unsung hero, year on year delivers all the biological data to tight deadlines for the students for their reports. We thank the many colleagues at GSK (listed in refs 8 and 9) who contributed to setting up and supporting the modules, Dr. Andrew Nortcliffe the current GSK Teaching Fellow, and the current mentors and teachers of the modules from GSK: Nick Barton, Stephen Swanson, Pan Procopiou, Katherine Jones, Ian Smith, Alan Nadin, and Ashley Hancock. We are grateful to Pippa Oxford and Christian Hoenig for their candid feedback on the modules. Finally we thank Professor Chris Moody at the UoN and Dr Harry Kelly at GSK for their support and guidance and particularly Sir Andrew Witty for the vision and funding.

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ABBREVIATIONS USED GSK; GlaxoSmithKline; UoN; University of Nottingham; CRO; contract research organization

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00198. Additional feedback from a University of Nottingham graduate on his experience of the module (PDF)

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REFERENCES

(1) Rafferty, M. F. No Denying it: medicinal chemistry training is in big trouble. J. Med. Chem. 2016, 59, 10859−10865. (2) Deloitte. 2016 Global life sciences outlook: moving forward with cautious optimism. https://www2.deloitte.com/content/dam/ Deloitte/global/Documents/Life-Sciences-Health-Care/gx-lshc-2016life-sciences-outlook.pdf (accessed November 2016). (3) PWC. Pharma 2020: From vision to decision. http://www.pwc. com/gx/en/industries/pharmaceuticals-life-sciences/pharma-2020/ vision-to-decision.html (accessed November 2016). (4) Allen, D. Where will we get the next generation of medicinal chemists ? Drug Discovery Today 2016, 21, 704−706. (5) In drug mergers, there’s one sure bet: the layoffs. Wall Street Journal 2014, http://www.wsj.com/articles/ SB10001424052702304393704579532141039817448. (6) Booth, B. Talent acquisition: pharma is the lifeblood of biotech. https://lifescivc.com/2014/05/talent-acquisition-pharma-is-thelifeblood-of-biotech/ (accessed November 2016). (7) Defined as achieving goals by approaching them indirectly or “goals [that] are best achieved without intending them” (James Black). See Kay, J. In Obliquity; Profile Books: London, U.K., 2011; pp xiii, 20−28. (8) Fray, M. J.; Macdonald, S. J. F.; Baldwin, I. R.; Barton, N.; Brown, J.; Campbell, I. B.; Churcher, I.; Coe, D. M.; Cooper, A. W. J.; Craven, A. P.; Fisher, G.; Inglis, G. G. A.; Kelly, H. A.; Liddle, J.; Maxwell, A. C.; Patel, V. K.; Swanson, S.; Wellaway, N. A practical drug discovery project at undergraduate level. Drug Discovery Today 2013, 18, 1158− 1158. (9) Macdonald, S. J. F.; Fray, M. J.; McInally, T. Passing on the medicinal chemistry baton: training undergraduates to be industryready through research projects between the University of Nottingham and GlaxoSmithKline. Drug Discovery Today 2016, 21, 880−887. (10) Belbin. Method, reliability & validity, statistics & research: a comprehensive review of Belbin team roles. http://www.belbin.com/

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +44 (0)1438 790495. ORCID

Simon J. F. Macdonald: 0000-0002-4859-8246 Notes

The authors declare the following competing financial interest(s): S.J.F.M. is a shareholder in GlaxoSmithKline. The authors are solely responsible for the content and the conclusions of this manuscript. All views expressed here are the opinions of the authors and should not be assumed to represent the views of either GlaxoSmithKline or the University of Nottingham. T.M. is a paid employee of the University of Nottingham, and S.J.F.M. is an employee and shareholder of GSK. Biographies Thomas McInally has over 30 years’ experience as a medicinal chemist in the pharmaceutical industry at Fisons, Astra Charnwood, and AstraZeneca and worked in various therapeutic areas. He joined the University of Nottingham as a Business Science Fellow in Medicinal Chemistry in September 2011 and is responsible for teaching and mentoring the fourth year M.Sci. students. Simon J. F. Macdonald has over 20 years’ experience as a medicinal chemist in the pharmaceutical industry and has spent his entire career at GSK in its various incarnations. He is currently Director of 7963

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Journal of Medicinal Chemistry

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media/1158/belbin-uk-2014-a-comprehensive-review.pdf (accessed May 2017). (11) This focus and sense of urgency illustrate the industrial approach: by the second week the students know what they are making and why and have started in the lab synthesising their first targets. (12) Adams, J.; Anderson, E. C.; Blackham, E. E.; Chiu, Y. W. R.; Clarke, T.; Eccles, N.; Gill, L. A.; Haye, J. J.; Haywood, H. T.; Hoenig, C. R.; Kausas, M.; Le, J.; Russell, H. L.; Smedley, C.; Tipping, W. J.; Tongue, T.; Wood, C. C.; Yeung, J.; Rowedder, J. E.; Fray, M. J.; McInally, T.; Macdonald, S. J. F. Structure Activity Relationships of av Integrin Antagonists for Pulmonary Fibrosis By Variation in Aryl Substituents. ACS Med. Chem. Lett. 2014, 5, 1207−1212. (13) Undergraduate chemistry students are able to enroll in this module for their fourth year project, and it took several years before it was accepted that it seeks to teach medicinal chemistry rather than synthetic chemistry. The emphasis is much more on making compounds for test as rapidly and as efficiently as possible so the students can analyze new SAR and design the next iteration of targets using a balanced and broad consideration of medicinal chemical properties. So rather than exploring novel synthetic methodology or ensuring exposure to a wide range of reactions, the students are encouraged to use standard robust reactions and to be less concerned with low yields (particularly late in the synthesis). Despite this, when we checked, the breadth of reactions used by the students was similar to those whose projects were synthetically focussed. (14) Tipping, W. J.; Tshuma, N.; Adams, J.; Haywood, H. T.; Rowedder, J. E.; Fray, M. J.; McInally, T.; Macdonald, S. J. F.; Oldham, N. J. Relative binding affinities of integrin antagonists by equilibrium dialysis and liquid chromatography-mass spectrometry. ACS Med. Chem. Lett. 2015, 6, 221−224. (15) Vallance, P. Industry-Academic Relationship in a New Era of Drug Discovery. J. Clin. Oncol. 2016, 34, 3570−3575. (16) The modules at the UoN are almost exclusively run (and more recently assessed) by GSK staff, the GSK Teaching Fellows, or a UoN Business Fellow, which indicates the degree of trust that exists with the UoN academics. (17) ICI was a major chemical company in the U.K. in the mid-20th century from which AstraZeneca eventually emerged. (18) Carney, S. Attracting and training the next generation of medicinal chemists, Drug Discovery Today, 2016, http://www. drugdiscoverytoday.com/view/44358/attracting-and-training-the-nextgeneration-of-medicinal-chemists/. (19) Lindsley, C. W. Lost in translation: the death of basic science. ACS Chem. Neurosci. 2016, 7, 1024. (20) Dodgson, M.; Gann, D. In Innovation: A Very Short Introduction; Oxford University Press: Oxford, U.K., 2010.

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DOI: 10.1021/acs.jmedchem.7b00198 J. Med. Chem. 2017, 60, 7958−7964