Leaders in Small Molecule Research and Discovery

Small Molecules: Here to Stay
Small molecules currently comprise the majority of marketed drugs. Of the top ten prescribed drugs in 2014, nine were small molecules. 161Although the largest pharmaceutical companies are increasing investment in specialty medicines, only about 30% of their pipeline products are biologics.162 The discovery and development of small molecules presents challenges to companies. Chief among these challenges is the time and financial investment required to discover and develop small molecules. Leaders in the discovery and development of small molecules are pursuing innovative strategies to maximize return on investment.

Focused investment
One strategy adopted by traditional pharmaceutical companies is to focus their investment resources allocated toward small molecules. In late 2015, Roche announced plans to restructure its manufacturing network for small molecules.163 The restructuring is designed to enable the company to manufacture a new generation of specialized therapies based on small molecules in lower volumes than traditional medicines.164 With the restructuring came the exit of 4 manufacturing sites, and the increased investment (approx. $304 million USD) in a single Swiss site.

Similarly, AstraZeneca announced a commitment ($50 million USD) to build an additional facility in Wuxi City, China, that will support the development and manufacture of small molecules discovered in their new Chinese and global research and discovery sites.165

New targets and new technologies
A second strategy adopted by diverse institutions employs innovative ways to make the discovery and development process of small molecules more efficient.

Genome-wide association studies (GWAS) identify genetic variations that are associated with a particular disease.166 The information may be used to better detect and prevent the disease.167 Leading research and treatment centers such as Brigham and Women’s Hospital, Harvard Medical School, and the Broad Institute have joined forces to use the information gleaned from GWAS to guide discovery. Recently, a collaboration between these institutions used GWAS results to guide the development of a drug-screen for the identification of small molecules inhibiting the CD40-CD40L intracellular signaling pathway – an important pathway implicated in rheumatoid arthritis.168

Ensemble Therapeutics, a biotechnology company, is attempting to build a molecular bridge between traditional small molecules and biologics in the form of synthetic macrocycles.169 Macrocycles, described as “small molecule biologics,” can interrupt protein-to-protein interactions, but are small enough to penetrate cell membranes.170 Ensemble’s anti-interleukin-17 is the first macrocycle discovered and developed using Ensemble’s proprietary technology.171 The company has formed strategic partnerships with large (Novartis) and mid-sized (Alexion) pharmaceutical companies to develop and market macrocycles.172

The Howard Hughes Medical Institute has recently developed a single automated process to synthesize 14 distinct classes of small molecules from the same building blocks. This innovative strategy has the potential to greatly simplify the chemical synthesis process.173 The technology behind the process has been likened to a 3-D printer for small molecules. The process creates efficiencies by capitalizing on the common structures found in many natural products, first teasing them out, and then rearranging them using a standard chemical reaction.174 This technology has the potential to enable access to many customized molecules on-demand.

Small molecules remain the backbone of clinical drug research and discovery. Leading companies and institutions alike are actively engaged in ways to improve the efficiency of small molecule production and maximize return on investment. Focusing resources for limited small molecule production is one strategy adopted by large pharmaceutical companies. Developing more efficient processes through technology or new targets is a second strategy adopted by diverse institutions including academic centers, privately funded research organizations, and mid-sized pharmaceutical companies.