An Inside Look into Designing Your Own Medicine

Our role is to find which protein/s are fundamental to disease, and then try to design medicines that only impact the relevant protein/s, sparing all the others in order to treat the disease without bringing unwanted side effects.  Combine this challenge with the need to manufacture and administer the drug safely, usually orally or subcutaneously, and ensure that it gets to the right places in the human body and the extent of the challenge is clear.  It is like finding a needle in a haystack.  That is why some of the best scientists in the world have dedicated themselves to discovering medicines – it is a great challenge but a great opportunity to make a difference to human health.

Fortunately, scientific and technological advances have made significant inroads to improving our ability to discover and invent medicines.  Capabilities such as functional genomics and induced pluripotent stem cell technology to produce disease-relevant patient-derived cells are broadening our understanding of human disease.  Technologies such as DNA-encoded libraries, chemical biology, RNA modulation and protein degradation are expanding the diversity of biological targets that we can work on.  And the promise of artificial intelligence and machine learning to build on the vast quantities of clinical and pre-clinical data to help enable smarter decisions around human translation, target selection and modality design could transform our future.

You have said that drug design is a “real art as well as a science in building medicines that do what we want them to do.” The path for obtaining the science-based grounding for this job is pretty clear. But where do I go to get the education and experience on the ‘art’ side of this profession. That’s fuzzier. Is it simply the school of ‘hard knocks’?

Designing medicines involves juggling many different parameters.  For example, to design an oral drug requires an understanding of how the drug interacts with the receptor, which can be enabled by understanding the structure of the receptor. But it also requires understanding how the body will distribute the drug, which is guided by the physiochemical properties of the drug.  For example, if drugs are too lipophilic, then they will be destroyed by the gut wall and liver and never get to the systemic circulation, but if they are too polar they will be unable to cross the gut wall to enter the systemic circulation.

We’ve learned about these properties through science—but where the art comes in is in the careful design required to balance all these things. In the example I just gave, we need to find enough lipophilicity, protected in the right way through the appropriate 3D molecular structure, to avoid metabolizing enzymes but still enable the drug to cross cell membranes.  Aqueous solubility and compatibility with formulation excipients are other important properties that need to be considered.  These properties all need to be optimized while maintaining potency and selectivity for the protein target.

These are just a few of the many parameters that need to be considered in the drug design world.  Reading up on the literature around drug design, and the associated technologies is a great way to learn.  But experience—in both the art and the science—plays a huge role in designing medicines, so seeking mentors with that expertise can be a very valuable approach and one that I have certainly benefitted from.  And yes, we all learn from our failures – they form part of our successes.

Among your scientists at Pfizer, what non-technical skills do you most highly value?

At Pfizer our primary stakeholders are the patients.  Patients are waiting for breakthrough medicines.  We hold this front and central to all the work that we do, and it brings an urgency and courage to our work that I highly value in our colleagues.

All scientists need to have integrity, resilience and tenacity to be successful.  In science we have many setbacks, and I really value colleagues who are transparent about their learnings, pick themselves up after a failure, take a step back and work out a new route to the goal.  We have to do this time and again in drug discovery, as continuous learning is part of our overall success.  

At Pfizer, our inventions and breakthroughs come from working in diverse teams of colleagues. Being able to collaborate broadly, listen to others’ views, advocate for your own, cut through the complexity to a clear plan and build trust through acknowledging the contributions of others are all skills that I see as instrumental to success.

What are some of the ways you try to develop and retain young talent at Pfizer?

Engaging emerging talent in cutting edge science and the design of medicines is a critical part of retention, as colleagues want to make a difference discovering the next wave of drugs. We provide a stimulating, scientific environment that encourages innovation and thoughtful risk taking so that new colleagues can build on their expertise and advance our programs.

At Pfizer, we have access to both state of the art as well as established technologies, giving colleagues access to great capabilities in the pursuit of medicines.  While it is important to deepen your discipline expertise early in your career to form a strong foundation on which to grow, we also ensure new colleagues get exposed to other scientific disciplines such as clinical sciences, disease area biology and drug safety amongst others.  This enables colleagues to benefit from our experienced drug discoverers, to stimulate their thinking and knowledge, but also grow their experience of working in the type of cross-disciplinary team that is essential to drug discovery success. 

Providing a flexible, fun working environment that enables all colleagues to thrive every day is also essential, as are competitive compensation and benefits packages.

What technology trends are you following most closely with an eye toward how they may impact the work of your scientists?

There are many – the current innovation explosion in biomedical sciences is truly exciting – but I will pick two:

Emerging approaches to modulating proteins:  The pursuit of breakthrough, transformational medicines is taking us into gene classes which have traditionally been hard to modulate using more conventional small molecule approaches, such as active site inhibition.  New approaches, such as targeted protein degraders both for intracellular and secreted proteins, RNA modulation, RNA and DNA epigenetic modulation, and selective small molecule protein translation inhibitors, amongst others, are important areas.  Ultimately, we want to be prepared to tackle any target that we believe is transformational to disease.

Therapeutic index enablers:  The search for transformational efficacy in our medicines will likely take us into “high horsepower” mechanisms where managing safety will be a challenge.  Designing molecules that distribute more to the site of action to achieve the desired efficacy and less to other parts of the body where we may see unwanted side effects, could make or break whether these mechanisms are druggable.  Approaches such as topicals as well as gut, tumor and liver targeting are already being pursued inside and outside of Pfizer, but emerging technologies including exosomes, organ-specific ligases for tissue-specific protein degradation, transporter-mediated cell specific uptake and prodrug strategies also hold great promise.

Pfizer’s CEO, Albert Bourla, was quoted in a recent issue of Barron’s: “The old model of pharmaceuticals that was based on blockbusters, physicians’ preference, or incremental innovation is turning now upside down.” He added, “The change is coming, and nobody knows how it will look.”  What impact does the disappearance of this old model have on the manner in which you execute your responsibilities?

Today both patient need and the resulting healthcare system is putting a greater emphasis on transformational, breakthrough therapies, and as such, we will see a higher proportion of first in class targets in our portfolio. In contrast to previous models that focused on strategies for established mechanisms, drug discovery in a first-in-class target world brings a greater emphasis on fundamental biology – understanding pathways and their role in the pathophysiology of disease, designing novel screening paradigms with a likely greater focus on phenotypic approaches, and truly novel hit identification strategies in an effort to identify lead compounds for currently un-drugged proteins. 

This challenge is likely to take us into new mechanisms of action, such as protein degraders and RNA modulators, and into different chemotypes.  These changes are influencing our investment strategies and provide truly exciting opportunities to our scientists to define the next wave of small molecule drug discovery.

What can the pharmaceutical industry do to make the workplace more welcoming and rewarding for women?

The importance of a diverse workforce both in order to represent modern society as well as for enhanced business performance is well understood, and I believe it is the responsibility of all leaders, regardless of gender or ethnicity, to commit to building an inclusive culture.  Being respectful of different styles of influencing, leading and approaching scientific problems is an important part of both diversity and inclusiveness.  Providing flexible working arrangements to allow colleagues to balance their home and work commitments enables talented individuals to thrive in work every day. 

Both my husband and I utilize the flexible working arrangements available through our employers to juggle the careers we enjoy with the needs of our four children who we enjoy even more, so this has been an important enabler for my career.

Building diverse teams and committees serves to inspire colleagues that inclusion is a reality. The role of the pharmaceutical industry in leading by example, investing in different hiring practices, as well as providing advocacy and mentorship for diverse talent, is an important part of this.  Within our department at Pfizer, we currently have a deep focus on these practices as well as job rotation and outreach opportunities, to ensure we build a culture where all colleagues can thrive.

How did your parents influence your leadership style?

I come from a farming background, and my parents instilled in me an incredible work ethic, through their dedication to their jobs, family and local communities.  They always met their commitments, acted with integrity and were respectful of others. I have been grateful for the values that they instilled in me, and the anchor of family that stays with me today.  My father was a true scholar too, reading avidly to continue to grow his knowledge on business as well as the countryside in which he worked, and that dedication to self-motivated, continuous learning has always inspired me.  We sit in control of our own learning.

You have said that your career advancement has been driven to a great degree by a constant desire to keep learning and find new ways to make significant impacts. How did that desire come to be within you? 

I was certainly inspired by my early experiences with medicines.  I grew up in a rural area of the U.K., and I suffered with asthma and allergic rhinitis.  Summer was hard work. The combine harvesters would be whirring and the dust billowing, and I would wheeze and sneeze my way through these months.

I remember very clearly the first time that I took the b2 adrenergic receptor agonist salbutamol and the antihistamine terfenadine, and within minutes I felt like a different person.  I was fascinated by what the drugs were doing and how they were getting to where they needed to be.  Of course, terfenadine went on to be removed from the market due to a drug-drug interaction, and its metabolite fexofenadine became a drug in its own right. 

This experience and the learnings around these medicines inspired a deep interest in me regarding the design of medicines, and a desire to try and make a difference for the next era of drug discovery.  Since joining industry, I have also been inspired by many of the colleagues from inside and outside of Pfizer who have made tremendous contributions to the field of drug discovery and development.

In the United States at least, the pharmaceutical industry is frequently attacked by politicians and the media for what they consider to be high prescription drug prices. What impact, if any, does this criticism have on the morale of your scientists, and how do you manage it?

Our scientists are passionate about innovating to bring new medicines to patients.  That is what motivates them day in and day out.  The pharmaceutical industry is part of a much larger scientific ecosystem focused on interrogating disease and bringing forward novel treatment options.  Ours is important and challenging work, which has a positive impact on human health, and colleagues are rightfully proud of their role in enabling this.

Drug pricing is a fast-evolving area, with Pfizer and others committed to working with regulators on payment models to improve patient access to our medicines both in the U.S.A. and around the world.  Of course, pricing also plays an important role in funding future innovations in research and development to enable the next wave of medicines, in a high attrition and costly industry.  Our scientists are driven to bring forward medicines as efficiently as possible to tackle the toughest healthcare challenges.  Keeping our scientists focused on this mission, and continuing to make a difference, helps transcend any dips in morale.

You are no stranger to excellent schools, having attended Cambridge and Nottingham in the U.K., and having spent many years working in a city that boasts Harvard and MIT, among others. Let’s take you back in time. You’re 18 again, and knowing what you know now, where would you most want to go to school as an undergrad, and as a grad student?

I can’t work out how to answer this without offending the great universities that I studied at!  Or the great many mentors and collaborators I have at many schools in the U.S.A. and beyond.  So, I will hedge my answer, and say that I would follow the same path, as I am truly grateful for the opportunities it has brought me to work on the design of meaningful medicines with many inspiring colleagues, in the hopes of changing patients’ lives.

And there are many different paths for students today to enter a career in drug discovery, across scientific, mathematical and other disciplines.  My advice would be to go deep in your discipline first, build that strong foundation on which to launch your career, and then start layering on the breadth of knowledge involved in drug discovery. 

Equally important to academic studies are the life experiences that you bring to your work – resilience, continuous learning, generosity and inclusiveness will stand students in good stead.  Seek diverse life experiences to expand your horizons and broaden your thinking. 

Charlotte joined Medicinal Chemistry in Pfizer, Sandwich in 1993, and spent 14 years working across a range of therapeutic areas, including a secondment to Japan. In 2007, Charlotte joined PDM, progressing to lead the Sandwich PDM group. She moved to Cambridge UK in 2011 to lead Pre-Clinical Sciences for Pain Research, overseeing DMPK, drug safety and pharmaceutical sciences. In 2012, Charlotte moved to the USA to lead small molecule PDM, and then in 2016 expanded her responsibilities to lead Medicine Design.

Charlotte obtained her BSc from the University of Nottingham in 1993 and MPhil in organic chemistry from the University of Cambridge in 1997.

This article has been edited for length and clarity. The opinions expressed in this article are the author's own and do not necessarily reflect the view of their employer or the American Chemical Society.

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