The Challenges In Small Molecule Drug Development – Part I

Jul 16, 2018 | Trends

The world of drug discovery is rife with new approaches within immunotherapy (e.g., T cell-based cancer therapies), personalized vaccines, microbiome therapies, and CRISPR-based therapies in an attempt to provide novel treatments and cures for a wide range of diseases, most often cancer. Despite the fact that progress is being made in these areas, with FDA-approval granted for the first two CAR T-cell therapies in 2017, more than 90 % of the drugs currently available on the worldwide therapeutics market is comprised of small molecules. This fact is further illustrated by the overwhelming presence of small molecule drugs in the World Health Organization’s Model Lists of Essential Medicines, lists containing “the medications considered to be most effective and safe to meet the most important needs in a health system”. 

What Are Small Molecule Drugs?

When we talk about small molecule drugs, we are referring to small, synthetic or naturally-derived chemical molecules generated by organic chemistry techniques, where drugs are produced in chemical reactors as opposed to in living cells or tissues. These molecules are often derived from or inspired by natural products produced by bacteria, fungi and plants, such as the antifungal amphotericin B, the antibiotic penicillin, and the chemotherapeutic paclitaxel, respectively.

Although small molecule drugs may sound old-fashioned in comparison to the popular therapies that dominate our media today, their importance cannot be understated. According to 2017’s figures on the sale of prescription drugs in the U.S., 9 of the top 10 selling-medicines were small molecules, representing painkillers, statins, blood pressure reducing medications, and antibiotics. It is also worth pointing out that while many of the best-selling small molecule drugs are “old” (indeed, aspirin has been around since the end of the 19th century!), small molecules deserve to take center stage in our current-day personalized approaches to medicine. One notable example is the FDA’s approval of ivacaftor for the treatment of subsets of cystic fibrosis (CF) patients with certain mutations in the CFDR gene. By harnessing knowledge about genetic variability in CF patients, ivacaftor (marketed as Kalydeco) could be realized as an effective and well-tolerated treatment for those CF patients most likely to reap the benefits.

Developing Small Molecule Drugs – is it JUST Old-Fashioned Chemistry?

Given the resilience of the small molecule drugs in the face of the complex cutting-edge therapies that are now beginning to emerge (CAR-T, biologics/PD-L, stem cell therapies, etc.), one might think that the development of the former was somewhat more straightforward or faster than the latter. This is very far from the case, and the challenges involved in small molecule drug development are highlighted by the fact that only 1 out of every 10,000 compounds synthesized will eventually obtain FDA approval1.

So why do drug developers continue to work with small molecules at all? Let’s look at some of their main benefits:

  1. Small molecules are relatively simple to manufacturer and scale-up, and quality control (QC) is fairly straightforward with well-established methods available in most cases.
  2. They are cheaper to produce than biologics.
  3. Millions of unique small molecules can be synthesized, creating endless possibilities for the design of new drugs.
  4. Flexibility of administration routes. Small molecules may be formulated as pills and capsules, intravenous or subcutaneous injectables, inhalational medicines, or suppositories, giving great flexibility in the clinic, for example, patients with swallowing difficulties do not have to take pills or capsules.
    Note: not all small molecules are amenable to all modes of administration.
  5. They can be reproduced as cheaper non-branded generics once the original drug patent expires, thus increasing their availability to patients, for example, through health insurers who often choose generic drug forms by default.
  6. Many of the signaling and inhibitory pathways within the body are driven by small molecules such as cyclic AMP, hormones, and neurotransmitters such as L-DOPA (a precursor to dopamine used in the treatment of Parkinson’s disease). Therefore, it seems logical to use what we know about the chemistry that exists in our natural world and find small molecules to address disturbances in these pathways.

Stay Tuned!

This series of articles aims to describe the process of bringing a small molecule drug from the lab bench to the clinical development stage, highlighting the challenges that may arise at each step. Figure 1 below gives a brief overview of the steps involved in this process. Stay tuned for the next installment where we will look at Target Identification and Assay Development & Validation and their associated challenges in more detail!

Figure 1. Overview of small molecule drug discovery and pre-clinical development

The process starts with the identification of a druggable target e.g., an enzyme implicated in a disease. Assays are then established to quantitatively monitor target activity in vitro, with robust positive and negative controls. During in vitro compound screening, compounds that exhibit promising activity may be subjected to secondary assays e.g., in vivo assays to study their safety and efficacy. The red arrows indicate that the screening and hit identification steps are iterative and may occur over several rounds. If no promising hits are identified, additional compound libraries may be screened. Once hits have been selected, they are subjected to structure-activity analysis to maximise their activity and drug-like properties. This eventually results in the identification of lead compounds, which are then optimized in vivo for safety and pharmacological properties. Lead identification and optimization are iterative processes that can occur over many cycles. Eventually, a candidate drug is identified for clinical development, and the drug developer seeks permission from regulatory bodies to include this drug in clinical trials with research subjects. This step is known as investigational new drug (IND) filing, and once approval is gained, the candidate usually enters a Phase 1 clinical trial.


  1. Pharmaceutical Research and Manufacturers of America (PhRMA), April 2014. 2014 Profile, Pharmaceutical Research and Manufacturers of America (PhRMA), Washington, DC.

Article by Karen O’Hanlon Cohrt PhD. Contact Karen at 

Karen O’Hanlon Cohrt is a Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD,  Karen moved to Denmark and held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for writing helps her to keep abreast of exciting research developments as they unfold. Follow Karen on Twitter @KarenOHCohrt. Karen has been a science writer since 2014; you can find her other work on her portfolio.