Behind the Scenes of Drug Discovery—Empowering employees to pursue a breakthrough
Proteins work in various ways in the human body and modifying disease-related proteins is a key strategy for pharmaceutical companies to develop effective drugs. While many drugs have been produced by chemical synthesis, they have been able to target only about 20% of disease-related proteins.
In recent years, new technologies have emerged that could also target the other 80% of proteins, and Astellas is excited to leverage this technology for new drug discovery. Dr. Masahiko Hayakawa, the head of Targeted Protein Degradation at Astellas, and Dr. Tomohiro Yoshinari, a research fellow in the same division, talked about how leadership encouragement brought one researcher's idea to life, galvanized R&D across the organization, and resulted in the creation of several drug candidates using this new technology.
Exploring the potential of Targeted Protein Degradation technology
Conventional synthetic drugs are designed to bind to the pockets of disease-related proteins and control their functions. However, this approach is only effective for about 20% of proteins, as the other 80% don’t have deep binding pockets for synthetic drugs to adequately control their functions. One example is KRAS, which plays a critical role in cell proliferation in the human body. When KRAS malfunctions due to various factors, it can lead to cancer. Astellas has long been devoted to developing synthetic drugs that can control the function of KRAS. Astellas was struggling to identify a drug candidate with sufficient efficacy.
In recent years, a new technology called targeted protein degradation has emerged. It can target the remaining 80% of proteins that are difficult to reach with conventional synthetic drugs. This technology works by leveraging the body's natural ability to accelerate the degradation of disease-causing proteins. Click here to learn more about how protein degraders work.
In such a situation, Dr. Tomohiro Yoshinari was thinking about how to apply this technology to control the function of KRAS.
"As I delved deeper into targeted protein degradation, I came up with a novel approach that might allow us to design protein degraders targeting KRAS protein . Therefore, I drew an image of a structural design, and presented it informally to the research unit head, Dr. Hayakawa. I was in an environment where I could freely share my thoughts and propose even small-scale ideas without having to create detailed presentations. Even though I wasn't confident in the feasibility of the concept at that time, Dr. Hayakawa encouraged me to pursue the idea."
Dr. Hayakawa reflects on those days. "I remember when Dr. Yoshinari showed me the image of structural design, and as soon as I saw it, I found it fascinating and encouraged him to proceed. In the past, implementing an idea in our research organization would take a long time due to the multiple approval steps involved, but the organizational reformation at the time allowed each research unit to make decisions, making the process much more agile. Once I gave the green light, we could immediately move forward.
Taking on the challenge as One Astellas
After only 5 months, we succeeded in synthesizing protein degraders that targets KRAS and identified a clinical drug candidate in January 2021. Typically, identifying a clinical drug candidate involves synthesizing hundreds or even thousands of compounds, a task that can take a significant amount of time. However, by leveraging our accumulated knowledge of KRAS research and the power of computers and AI, we were able to identify the 38th compound as a drug candidate in an exceptionally short time. Within a year, Astellas submitted an Investigational New Drug (IND) application to the U.S. FDA, marking an unprecedented speed of development.
When asked about the background of this success, Dr. Hayakawa said, “The journey toward submitting an IND began with the Research division proposing a very challenging schedule to other divisions including development and manufacturing. Based on my past experience with IND submissions, I knew how much effort was required to make it work, and, at first, the other teams wondered if it was really possible. However, each division was proactive in thinking about how they could contribute to the project’s success and moved forward together.”
In the past, drug development advanced by passing the baton between divisions, but this time, cross-functional team worked together from an early stage toward a common goal.
Delivering new VALUE to patients
Dr. Hayakawa believes that targeted protein degradation is a promising technology that will revolutionize the field of synthetic drugs and usher in a new era. "Since the technology is based on synthetic drugs, Astellas can leverage its accumulated knowledge and experience in this field to its advantage. In addition, we have many experts in the area of synthetic drugs. We will proactively leverage the strengths of our external partners while harnessing the expertise of each researcher through our flexible organizational structure. We aim to lead the industry with targeted protein degradation technology and want to create VALUE for patients."