Chemistry and Pharmacology of Drug Discovery
Jie Jack Li, Adjunct Professor, University of Michigan
Description:
Chemistry and Pharmacology of Drug Discovery illustrates how chemistry, biology, pharmacokinetics, and a host of disciplines come together to produce successful medicines, discussing a total of 20 drugs that are all FDA-approved post-2021, some of which are first-in-class and revolutionary.
The four sections in this book cover Infectious Disease, Cancer Drugs, CNS Drugs, and Miscellaneous Drugs. Each chapter covers background material on the drug class and/or disease indication and key aspects relevant to the discovery of the drug, including structure-activity relationships, pharmacokinetics, drug metabolism, efficacy, and safety.
1. Your book explores 20 FDA-approved drugs post-2021. What was your selection criteria for including specific molecules, and how do they collectively reflect the current landscape of drug discovery?
Most of them are best-selling small molecule drugs although an orphan drug is also covered for breadth. Some are the first-in-class drugs and many are the best-in-class drugs. However, some of them are chosen to be highlighted due to their novel mechanism of action and interesting DMPK properties that were highly publicized. We have also added a cyclic peptide drug to increase the diversity.
As a result, this book covers drugs from three major therapeutic areas: infectious diseases; oncology; and CNS drugs. In addition, we also covered two miscellaneous drugs: one for treating female HSDD and an orphan drug for treating familial intrahepatic cholestasis.
2. The text integrates chemistry, biology, and pharmacokinetics. In your view, how has the interplay of these disciplines evolved in recent years compared to earlier eras of drug development?
A significant change is the use of CROs. Although not covered in the book per se, more and more portions of drug discovery and development have been sourced out. I personally favor keeping a certain proportion of research internally because some Eureka! Moments can only arrive when doing it your selves.
3. Many of the drugs covered are first-in-class. What does this reveal about the current innovation cycle in pharmaceutical R&D - are we witnessing a paradigm shift toward more groundbreaking therapies?
By definition, first-in-class drugs are more challenging, often taking longer time. While groundbreaking therapies benefit patients, ironically, first-in-class drugs might not be financially most successful. Consequently, best-in-class drugs may bring more financial rewards. Big pharma thus wisely pursues both first-in-class and best-in-class drugs. For smaller biotech companies, it might be easier to attract investment with novel targets. But I see some of biotech companies actively pursue a “fast follow” strategy as well.
4. The book addresses infectious disease, cancer, CNS disorders, and miscellaneous indications. What guided the decision to focus on these four therapeutic categories, and how do they represent the “frontlines” of modern drug discovery?
Indeed, the three therapeutic areas in infectious disease, cancer, and CNS disorders are more prolific recently. Cardiovascular disease area is relatively quiet lately probably because we already have many efficacious and safe drugs. In terms of antibiotics, we certainly need drugs with novel mechanisms because of drug resistance issues is becoming epidemic. Unfortunately, antibiotics are not profitable and hard to attract investment. Discovering a bad antibiotic, nobody will use it. Discovering a good novel antibiotic, few will use it because doctors want to keep it as the last line of defense. Therefore, Gates Foundation and other philanthropic organizations might be a good direction to go.
5. Could you elaborate on how the discussion of structure - activity relationships (SAR) in your book bridges theoretical chemistry with real-world therapeutic impact?
Good question. For structure-activity relationships (SAR), it was historically explored “blindly” by trial and error. An analogy of blind people feeling the elephant comes to mind. However, with availability of X-ray crystallography, we can do rational drug design with relative ease. Cryo-electron microscopy (cryo-EM) has further expanded the repertoire of target structures. More excitingly, artificial intelligence (AI) such as AlphaFold3 can offer exponentially expanded potential target structures that could revolution the way we carry out structure-activity relationships (SAR).
6. Pharmacokinetics and drug metabolism often determine a molecule’s fate in development. What are some of the recurring lessons or surprising insights from the drugs you analyzed?
Much has changed for drug discovery in recent years compared to earlier eras of drug development. For instance, DMPK has been placed in an appropriately more important emphasis. We now value bioavailability as important as potency after many failures. One important realization is that Lipinski’s role-of-five covers a smaller portion of drugs than initially supposed. Therefore, beyond-rule-of-five drugs have flourished.
7. Efficacy and safety are highlighted in each chapter. How do you illustrate the often delicate balance between these two aspects in the success or failure of recent FDA-approved drugs?
While regulatory agencies look at numerous aspects of a drug, two attributes are most important: efficacy and safety. Granted, a highly efficacious drug generally has better safety profile because of low dosage. Nevertheless, more drugs fail due to safety issues because drugs do not show efficacy in phase II clinical trials although there are conspicuous failures due to lack of efficacy in Phase III clinical trials.
8. Cancer therapies are evolving rapidly, from small molecules to biologics and targeted agents. What key chemical principles do you highlight in your book that remain central to advancing oncology drug discovery?
Although this book covers only small molecular drugs, biologic cancer drugs are becoming more and more important. In fact, the best-selling cancer drugs are PD-1 inhibitor pembrolizumab (Keytruda), a monoclonal antibody as a cancer immunotherapy. Excitingly, ADC drugs are also contributing to cancer treatment. In addition, gene therapy such as CAR-T cell therapy and others are making great impact.
9. For CNS drugs, challenges like the blood–brain barrier remain daunting. How do the examples in your book demonstrate innovative strategies to overcome these hurdles?
The BBB issue is now well understood. Smaller and more lipophilic molecules are better brain penetrants. But transporter substrates are also prone to cross BBB.
10. Infectious disease has re-emerged as a global R&D priority after COVID-19. Based on the drugs you cover, what new chemical and pharmacological approaches are shaping this field?
We have come a long way with regard to antiviral drugs. The latest innovation is combination drugs that combine two or three drugs with different mechanisms of action. By attacking the virus by several targets simultaneously, the drug is more efficacious and safer if the toxicities are not synergistic for each of the ingredients.
To learn more on antiviral drugs, please check out a recent book of mine on the topic:
Conquest of Invisible Enemies—A Human History of Antiviral Drugs Jie Jack Li, Oxford University Press: New York, NY, 2022.
11. The "Miscellaneous Drugs" section suggests diversity beyond major therapeutic areas. How do these examples reflect the breadth of chemical innovation in drug discovery today?
Peptide drugs are seeing a reconnaissance. A peptide drug for treating female HSDD is an eye opener. Even though we have many drugs to control cholesterol levels, there are still unmet medical needs. We covered an orphan drug for treating familial intrahepatic cholestasis. Working with orphan drugs is a good venue for small biotech companies to get the food in the door before embarking on projects that are more ambitious.
12. Many readers of your work will be practicing scientists. How does your book aim to provide not only educational value but also practical guidance for current and future drug discovery projects?
Confucius said, you learn something anytime you crack open a book. Drug discovery is such a complicated process that involves so many disciplines that practitioner need to be cognizant of all the “periphery” fields such as biology, DMPK, and toxicities. It is knowledge-accumulation that I hope this book will help. You learn one thing here and one thing there, soon you get to know the bigger picture of drug discovery.
13. Finally, what overarching message do you hope readers - whether chemists, pharmacologists, or interdisciplinary scientists - take away from Chemistry and Pharmacology of Drug Discovery about the future of medicine?
Again, every scientist in the field of drug discovery and development must learn other relevant disciplines other than his/her own. This is the take-home message that I hope the book sends. Take myself as an example. When I started in the business as a medicinal chemist in the 1990s, all I knew was synthetic organic chemistry for making drugs. However, since then, I find myself, though reading and writing books such as this one learn more and more about pharmacology, DMPK and safety in order to do a better job.
Nowadays, it is especially true to know every aspect of drug discovery in the era of CRO proliferation. Many “wet” experiments can be outsourced therefore, a project leader must be equipped with knowledge to deciphering data of all fields and design the next rounds of drugs. It has been a joy to learn and to write on these topics for my coauthors, and me I hope the reader will feel the same.
The future of medicine will benefit from the proliferation of AI, for sure. Biologic drugs seem to be outpacing small molecule drugs in terms of profit. Too many virtues associated with small molecule drugs making them indispensable. So medicinal chemists are still indispensable although our knowledge constructs may evolve as the world of medicine evolves.
Author Bio
Dr. Jie Jack Li is an Adjunct Professor at the University of Michigan. He has over 30 years of experience in medicinal chemistry and drug discovery, spanning both major pharmaceutical companies and biotechnology firms, including Pfizer and Bristol Myers Squibb. He also spent four years as an Associate Professor at the University of San Francisco. Dr. Li has authored more than 35 books on organic chemistry, medicinal chemistry, and the history of drug discovery, 10 of which were co-authored with Nobel Laureate E.J. Corey.
