A big future for small molecules: targeting the undruggable

Small molecule drugs have been the mainstay of the pharmaceutical industry for nearly a century. Defined as any organic compound with low molecular weight, small molecule drugs have some distinct advantages as therapeutics: most can be administered orally and they can pass through cell membranes to reach intracellular targets. They can also be designed to engage biological targets by various modes of action and their distribution can further be tailored, for example to allow for systemic exposure with or without brain penetration. 

The rapid advancement of biopharmaceutical research and technology opens up possibilities for innovative and creative new approaches to developing small molecule drugs. At AstraZeneca, we combine our unique range of knowledge, skills and experience across multiple disciplines to keep discovering and developing potential new small molecule therapeutics. This includes utilising high-throughput screening, ensuring multifaceted characterisation of the molecules’ engagement with their targets and having deep expertise in chemical synthesis. In recent years, advancements in predictions, structure-based design and imaging together with automation1, artificial intelligence and machine learning, have become important enablers to gain speed and improve the success rates of small molecule lead optimisation.

We are constantly advancing our capabilities to create new potential therapies for the future. For example, modulating biological disease driving pathways at the RNA level opens up new opportunities for previous undruggable targets and we are exploring the potential to use small molecule drugs to target RNA. New research we carried out in collaboration with the lab of Matthew Disney, PhD, at Scripps Research in the USA, and which was published in Nature Chemistry, describes the discovery of small molecules that are able to restart cellular production of vascular endothelial growth factor A (VEGF-A) in cellular models.2 VEGF-A is key to rebuilding blood vessels and muscle in damaged heart tissue and improving blood flow.

The ability to design small molecules capable of interacting with and modulating RNA could open new avenues to target challenging disease pathways that have previously been considered undruggable.

Malin Lemurell Executive Director and Head of Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D

Other creative approaches we are exploring focus on the use of nanoparticles to direct small molecule drugs to specific cell types or minimise potential side effects.3


1. Friis S, Johansson MJ, Ackermann L. Cobalt-catalysed C-H methylation for late stage drug diversification. Nature Chemistry. 2020. 12, 511–519.

2. Haniff HS, Knerr L, Liu X et al. Design of a small molecule that stimulates VEGFA informed from an expanded encyclopedia of RNA fold-small molecule interactions. Nature Chemistry. https://doi.org/10.1038/s41557-020-0514-4

3. Tyagi P, Pechenov S, RiosDoria J et al. Evaluation of Pyrrolobenzodiazepine-Loaded Nanoparticles: A Targeted Drug Delivery Approach. 2019. 108(4): 1590-1597.

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