[WuXi AppTec]
Small-molecule drugs have advantages and disadvantages when treating cancer. Their low molecular weight means they can penetrate cell membranes and enter cells, allowing for highly targeted interactions that can directly disrupt intracellular processes.
However, these drugs do come with complications. They can have more unintended consequences than biologics, which makes rigorous testing even more important.
Breakthroughs in small molecule oncology drugs
Since 2001, small-molecule inhibitors have been developed to offer targeted therapies to cancer patients and have proven highly effective. However, there have been issues with drug resistance, where cancer cells can create mutations that alter the structure of the target protein, making the inhibitor ineffective. Other challenges include off-target effects and the requirement of frequent dosing.
One of the significant breakthroughs in small-molecule oncology drugs is protein degraders. These drugs attempt to eliminate specific disease-causing proteins from cells. One of the most promising types of protein degraders is Proteolysis-Targeting Chimeras, better known as PROTACs.
PROTACs have two heads connected by a linker. One of these heads binds to the target protein, and the second enables the protein to be targeted for degradation by the ubiquitin-proteasome system. The first PROTAC degraders entered clinical trials in 2021, and more are keenly anticipated as potential solutions to previously undruggable conditions.
Molecular glues are an even more novel concept. They are also small molecules that induce protein degradation by modifying how the target protein interacts with an E3 ligase. They are smaller than PROTACs and are considered more subtle in their work.
Protein degraders boast some critical advantages over inhibitors. First, they degrade the protein completely rather than inhibit it, and resistance to the drug does not occur in the same manner. They also have lower toxicity and target proteins that other drugs cannot.
Navigating regulatory pathways
As advances in small-molecule oncology drugs continue, sponsors and developers must appreciate the differences in the regulatory process for these drugs compared to non-cancer pharmaceuticals.
The fundamental difference between oncology and non-oncology drugs in the regulatory process is their attitude to risk. There is a far greater acceptance of risk when developing oncology drugs, because they are tested on advanced cancer patients. This is partly due to the nature of oncology drugs. If a drug is designed for a condition such as arthritis, the emphasis is on making it as safe as possible for potential long-term use. However, oncology drugs need to be toxic if they are to have any impact on tumor cells, so regulators need to tolerate more risk when assessing these drugs.
This attitude has a knock-on effect on testing goals, too. Generally, the primary objective of Phase 1 testing for drug development is to establish safety. However, with oncology drugs, that goal is somewhat different. Safety is paramount, but developers and regulators are also seeking strong efficacy. The urgent need for cancer therapies is another factor making regulatory approval quicker. For conditions that are highly contagious or deadly, regulators often streamline the requirements so that drugs can reach the market and patients faster.
However, this only applies to cancer drugs if the Phase 1 trial is planned for advanced cancer patients. The streamlined route through regulations is reserved only for the treatments tested first on patients with advanced cancer.
Small-molecule oncology drugs can be tricky because they operate inside the cell, sometimes creating more unintended consequences than large molecule drugs. Drug developers looking to make the most of possible fast-track approval possibilities—and avoid the pitfalls—must ensure they have the required experience and expertise or work with a lab partner who does.
Making the most of a golden age
Introducing new chemistry including protein degraders can usher in a new age for small-molecule anti-cancer drugs. The increase in computing power and technological progress in machine learning can also ensure that any new drugs coming to market can do so quickly with fewer resources. The potential impact of more effective, cost-efficient, and rapidly rolled-out cancer drugs would be astronomical.
For developers, we’re entering a golden age of small-molecule medicine. Many pharmaceutical companies bringing small-molecule drugs to the market may be small, and some may even have only one drug candidate in their portfolio. This makes it even more important that they prepare properly for a smooth regulatory journey.
About the author
Tina Rogers, Ph.D., DABT, MBA
She has served as an advisor and driven growth and profitability in all of her leadership roles. Dr. Rogers holds a doctoral degree in molecular and cellular biology and pathobiology from the Medical University of South Carolina and an M.B.A. from Auburn University. She has a broad technical background, including cell biology, immunology, toxicology, cell and gene therapy, sepsis, inflammation, BL-3 and select agents, flow cytometry and predictive/in vitro toxicology. Dr. Rogers also serves as a board member for several biotech, academic and not-for-profit institutions and is a Diplomate of the American Board of Toxicology (DABT).
Filed Under: Oncology
