Small Molecules: Shaping Drug Discovery and Clinical Research

Small Molecules as Means to an End
Small molecules have driven advancement in preclinical and clinical drug development. Beginning with salicylic acid, isolated from willow bark, small molecules overwhelmingly represent currently marketed therapeutics.148

While in many cases, an effective small molecule treatment is the output of many years of research, small molecules are used extensively to achieve milestones along the pathway from discovery through development, and clinical trials. For example, small molecules can be critical assets during the target validation phase by acting as positive or negative controls in assay development, or as tools in counter screening to check for undesired properties. 149 Some small molecules such as colchicine are approved therapies (gout in this case), but are also used as a research and discovery probe. Colchine is valued during the R and D process because it alters the polymerization of primary cytoskeletal structural components.150

Small Molecules as Clinical Trial Controls
Small molecules have shaped clinical trial design and research policy. Early clinical trials, although relatively controlled, were designed around the available alternatives to the treatment. They offered more scientific evidence than the typical decision rubric of anecdotal experience. The UK Medical Research Council (MRC) significantly advanced clinical trial research in the 1940s by conducting a randomized trial of streptomycin in pulmonary tuberculosis. This trial had strict enrollment criteria, and patients were allocated and evaluated in more objective ways by parties blind to the treatment.151 At that time the comparator was no treatment.

With the advent of ethical parameters and codes to protect human subjects, small molecules became more prominent in trial design as comparators. Modern clinical trials in more severe diseases (e.g., cancer) compare a proposed drug with standard of care. The standard of care, typically a small molecule with established efficacy in the disease, sets the benchmark by which the efficacy and safety of the new product are judged.

Small Molecules and Drug Approval Policy
In direct response to the mounting evidence of teratogenic effects of the small molecule, thalidomide, the 1962 Kefauver-Harris Amendments required more transparency in clinical trial design, continuous monitoring and reporting of ongoing clinical trials and tighter tracking of drug distribution.152 The circumstances surrounding thalidomide fundamentally changed the way clinical trials are conducted in the United States and elsewhere in countries with approval programs and processes similar to those of the US Food and Drug Administration. Following the thalidomide tragedy, manufactures must prove the safety and efficacy of a new product before the drug could receive approval for marketing and distribution.153 In this way, governmental policy in the US changed as a direct result of the influence of a small molecule.

Inflammation, Small Molecules’ Home Turf
The anti-inflammatory properties of willow bark led to the discovery and development of aspirin — one of the first, and most successful small molecules ever marketed. Inflammation remains a widespread problem and is hypothesized to be the root cause of many chronic diseases and aging.154,155 New small molecule therapies in preclinical development have been shown to reduce inflammation and rejuvenate aging muscle and brain tissue – essentially stopping the aging process within cells. The newly discovered small molecule drug inhibits the effects of transforming growth factor beta-1 (TGF-beta 1), a protein that prevents stem cells from renewing tissue.156 It may be too soon to christen the drug a “fountain of youth”, but the discovery of a single small molecule that simultaneously rescues functioning in aged brain and muscle tissue, may be one step closer.

Small Molecules, Big Future
Small molecules have been the most widely marketed, developed, and used therapeutics in modern medicine. Most currently marketed drugs are small molecules and their usefulness continues to expand as medicine discovery techniques advance. The first marketed small molecules were derived from plants and ameliorated inflammation. Science has come full circle – trending medicine targets include optimal gut biome functioning and inflammation suppression. Many dollars are being spent to determine how these two systems are linked, what the impact is when they are not in balance or functioning properly, and how chronic dysfunction contributes to disease157. Small molecules hold the key to these future discovery pathways in medicine – small molecules from diet stimulate activity within the gut microbiome and may be transformed in the biome to inhibit inflammation.158 Small molecules also offer templates from which new drugs may be developed to combat the diseases linked to gut microbiome imbalance — autoimmune disease, cancer, obesity, diabetes.159  Small molecules freely enter Gram-positive bacteria, and molecules <700 Da can enter Gram-negative bacteria through porin proteins.160 The flexibility of small molecules to facilitate new drug discovery and development and serve as a template for new therapeutics point toward the big role they will continue to play in the future of medicine.