What are small molecule drugs?

Small molecule drugs are a class of therapeutics that are known to have low molecular weights, generally less than 900 Da, that can easily permeate cell membranes. Their ability to readily cross membranes makes them a cornerstone of modern medicine. In fact, up to 90% of drugs sold around the world today are small molecule.

Small molecule drugs have long been valued for their versatility, ease of administration and well-established regulatory and manufacturing requirements. They remain central to drug discovery and development across broad therapeutic areas, from over-the-counter pain relievers to targeted oncology treatments, even as biologics and other modalities become increasingly prominent. 

Today, small molecule drugs are becoming even more complex, with more intricate chemical structures and new modes of action, introducing significant development challenges. In this article, we’ll discuss how small molecule drugs work, explore some of their most important advantages, surface some of their challenges, and highlight how the right partner can streamline every stage of small molecule discovery through commercial manufacturing.

How do small molecule drugs work?

Unlike large molecules, also known as biologics, which typically target proteins or circulating molecules outside of a cell, small molecules bind to specific targets inside of a cell, such as enzymes or receptors. Once they reach a target, small molecules can inhibit or activate biological processes to achieve a desired therapeutic effect. 

As small molecule drug development has evolved, many of today’s compounds often bring greater structural and synthetic complexity. Therefore, striking the right balance of potency, selectivity, safety and efficacy has become increasingly challenging, particularly when working with emerging modalities like covalent inhibitors and proteolysis-targeting chimeras (PROTACs).

As they are generally orally bioavailable, small molecules are typically administered as pills or tablets, which tend to be more convenient than injections or infusions. Beyond their ease of administration, some other key benefits of small molecule drugs include: 

• Cell permeability: Small molecule drugs can often target cells that biologics cannot reach due to their small size. 

• Versatility: Small molecules can be designed to target a variety of biological processes, making them relevant for a broad range of therapeutic areas. 

• Cost-effectiveness: Small molecule drug synthesis tends to be more cost-effective and scalable than large molecule manufacturing. 

Well-understood regulatory requirements: Due to their longevity, small molecule drugs tend to have more established regulatory frameworks and standardised development processes, allowing for a clearer path to market.

What are small molecule drugs used for?

Even amid the growing prominence of biologics, the versatility of small molecules has kept them at the forefront of modern drug development. They can be designed to act on a wide range of targets, and are therefore used across nearly every therapeutic area, including:

• Pain management medications, such as ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs)
• Infectious disease treatments, including antivirals and antibiotics
• Cardiovascular treatments, like beta-blockers and Angiotensin-Converting Enzyme (ACE) inhibitors
• Neurological medications, such as antidepressants
• Oncology therapeutics, especially targeted inhibitors

Today, new modes of action have made small molecule drugs even more widely applicable. Some examples of innovation in small molecule development include covalent drugs, which can bind to active sites in proteins, and induced-proximity targeting, like PROTACs, which can tag target proteins for degradation. Advancements such as these have expanded the horizons of what small molecule drugs are able to achieve, but also require increasingly sophisticated synthetic and analytical methods, particularly in fields like oncology and precision medicine.

The small molecule drug discovery and development process

The lifecycle of a small molecule drug is marked by several important phases, which can be iterative during early phase discovery and development. We summarise these phases below: 

• Target identification: Scientists select a molecular target based on the therapeutic effect they want the small molecule drug to deliver. 
• Hit-to-lead optimisation: Scientists leverage high-throughput screening and computational methods to explore compound libraries and identify hits that interact with the specified target molecules in a promising way, then refine them into lead compounds by improving potency, selectivity and other pharmacokinetic properties. 
• Preclinical studies: Scientists perform in vitro and in vivo testing on the optimised leads to understand toxicity, absorption and other factors, and evaluate their suitability for use in human clinical trials. 
• Clinical trials: The drug candidate progresses through phase I, II, and III clinical trials, with expanding patient populations. While Phase I focuses on the first successful scale-up, Phase II focuses on thorough process development, and Phase III focuses on analytical method development and validation. 
• Final regulatory submission: The drug developer compiles comprehensive data on quality, safety and efficacy based on internal testing and clinical trials, then submits them to regulatory agencies for approval. 

Commercial manufacturing: Once approved, the product is manufactured in a large-scale, GMP-compliant facility on an ongoing basis, with continued process improvements as needed.

Challenges in small molecule development and manufacturing

Due to the increasing complexity of small molecule drugs, and an increasingly competitive market, any inefficiency in the development process can create delays and cost overruns. Today’s molecules increasingly feature intricate structures, potent intermediates, and new mechanisms of action that require advanced capabilities. 

Some key challenges include: 

• Synthetic complexity: Multi-step syntheses can be more difficult to optimise and scale.
• Target selectivity: Amid the importance of highly targeted therapies, achieving the desired efficacy without unwanted side effects has become more complicated.
• Evolving regulatory expectations: Regulatory agencies often expect more robust chemistry, manufacturing, and controls (CMC) data at earlier stages of development.
• Outsourcing fragmentation: Relying on multiple partners for different stages of the molecule lifecycle can result in additional technology transfers, knowledge gaps and general misalignment.

All of these challenges can lead to added costs and extended timelines if not navigated properly. As a result, choosing an experienced partner with integrated, end-to-end capabilities can mitigate these risks and accelerate time to market.

Small molecule API development and manufacturing at Sterling

At Sterling, we know that bringing effective small molecules to market demands more than equipment and capabilities. It requires end-to-end expertise and partnership across the entire small molecule drug lifecycle. 

We provide expertise from early phase discovery, route design and process optimisation through to GMP commercial-scale manufacturing, plus everything in between. Across our global network of facilities, our experience spans complex and hazardous chemistry, analytical method development and execution, regulatory and CMC support, and much more. This full molecule lifecycle approach enables us to help our customers contain costs, improve efficiency and accelerate time to market for their small molecule drug projects.

Above all, we treat our customers’ products as our own, and we are committed to delivering high-quality results in every project we encounter. By working with Sterling, our customers benefit from more than our services. They gain true partnership and expert guidance at every stage of small molecule development and manufacturing.

If you’d like to learn more about our small molecule drug development process and how we can support your specific project requirements, speak to a member of our team.