Many of humanity’s most impactful pharmaceuticals, including penicillin and aspirin, are small-molecule drugs. Over time, the focus of research has shifted toward biologics, also known as large-molecule drugs. In 2016, for example, eight of the 10 best-selling drugs in the world were biologics. However, small-molecule drugs are now making a comeback as research advances and technology improves. One key area where small-molecule drugs are making the most significant impact is oncology.
Small-molecule drugs offer advantages and disadvantages when treating cancer. Because of their low molecular weight, they can penetrate cell membranes and enter cells more easily, allowing for highly targeted interactions that directly disrupt intracellular processes. Small-molecule drugs also have complications. They can cause more unintended consequences than biologics, which makes rigorous testing more important.
The recent evolution of small molecule oncology drugs
Small molecule drugs, which have evolved over several years, are currently some of the most complex products in development:
Small-molecule inhibitors
Since 2001, tremendous progress has been made in developing small-molecule inhibitors that offer targeted therapies to cancer patients. These therapies have proved highly successful, but there have been issues with drug resistance, as cancer cells can create mutations that alter the structure of the protein being targeted, rendering the inhibitor ineffective. These drugs have also struggled with off-target effects and a reliance on frequent dosing.
PROTACs
Proteolysis-targeting chimeras, or PROTACs, are a type of protein degrader that attempts to eliminate disease-causing proteins from cells. They have two heads connected by a linker. One of these heads binds to the target protein, and the other enables the protein to be earmarked for degradation by the ubiquitin-proteasome system. PROTAC degraders first entered clinical trials in 2021, and their development is keenly watched as they can potentially treat conditions previously thought undruggable.
Molecular glues
Molecular glues are an even more novel concept than PROTACs. They’re also small-molecule protein degraders but modify how the target protein interacts with an E3 ligase. Molecular glues are smaller than PROTACs and are considered more subtle in their work, as they stabilize protein interactions. Protein degraders boast critical advantages over inhibitors. They degrade the protein rather than inhibit it, meaning resistance to the drug cannot occur in the same manner. They can also target proteins other drugs cannot and have lower toxicity.
Regulatory pathways: oncology vs. non-oncology
Advances in small molecule drugs are continuing rapidly, so sponsors and developers must be prepared to navigate the regulatory process for these drugs. Particular attention must be paid to the differences between regulation for oncology drugs and non-cancer pharmaceuticals.
When regulators assess non-oncology drugs, their attitude towardsrisk differs from cancer products. There is a far greater appetite for risk when developing oncology drugs because they are tested on advanced cancer patients and due to the nature of cancer as a disease. A drug designed for oncology needs to be toxic if it can make any impact on tumor cells, so more risk is tolerated when assessing these therapies. However, for a condition such as diabetes, the emphasis is placed on making it as safe as possible for long-term use.
This increased appetite for risk affects testing goals. Usually, the primary objective for Phase 1 testing is to establish safety. However, with oncology drugs, the goal changes. While safety is still paramount, developers also seek strong efficacy.
Oncology drugs can also benefit from a streamlined regulatory process to reach patients faster. This only applies to drug candidates that are tested on advanced cancer patients in Phase 1 trials.
Navigating these complexities and fast-track possibilities requires expertise and experience. Developers may need to collaborate with a lab partner to ensure submissions are approved quickly as they have the knowledge and capability to address any regulatory hurdles as they emerge. A trusted lab partner can also ensure developers make the most of any streamlined pathways and can cut down on time and expense during the submission process.
A Final Word
This could be a golden age for small-molecule oncology drugs. As new therapies enter clinical trials, increased computing power and technological progress in machine learning can accelerate their development further. A new wave of effective, cost-efficient cancer drugs would bring hope and relief to patients worldwide.
If these therapies are to reach the marketas quickly as possible, drug developers must ensure they are fully prepared for any challenges, including regulatory hurdles. By working closely with a trusted lab partner, sponsors can ensure they have the expertise, experience, and knowledge required to make the most of this opportunity.
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