Still Small, Still Mighty: Rethinking Small Molecules in Drug Discovery

"Small molecules may be small in size, but their impact on medicine is anything but." — Michelle Southey & Michael Brunavs, Evotec UK. In the age of biologics, RNA therapeutics, and cell-based interventions, small molecules are often perceived as legacy tools. But this view is increasingly outdated. Small molecules are not only enduring—they’re evolving, integrating, and in many cases, outperforming. Let’s explore why they remain foundational to drug discovery and how they’re being reimagined for the future. What Makes Small Molecules Mighty? Small molecules are low molecular weight compounds (<900 Da) that can modulate biological processes by binding to proteins, nucleic acids, or other cellular components. Their defining advantages include: Oral bioavailability and ease of administration Cell permeability, allowing access to intracellular targets Synthetic tractability, enabling rapid iteration and optimization Scalable manufacturing, supporting global access and affordability As noted by Southey and Brunavs, “Small molecule drugs are synthetic medicinal chemicals designed to mimic, enhance, or diminish the behaviour of natural substances… Their behaviour in vivo is usually predictable, leading to straightforward, often oral, dosing protocols that patients find easy to manage”. Comparative Landscape: Modalities at a Glance Article content Despite the rise of newer modalities, small molecules still account for over 90% of marketed drugs. Their ability to permeate cells and modulate intracellular targets remains unmatched. Strategic Scope in Modern Drug Discovery Small molecules continue to dominate in key therapeutic areas: Oncology: Kinase inhibitors (e.g., imatinib), PARP inhibitors (e.g., olaparib), and covalent KRAS inhibitors (e.g., sotorasib) Neurology: GPCR modulators, ion channel blockers Infectious Diseases: Protease inhibitors (e.g., nirmatrelvir), antivirals Metabolic Disorders: Enzyme modulators, nuclear receptor ligands Case in point: Revumenib (Revuforj®), a first-in-class menin inhibitor for KMT2A-driven leukemia, was approved in 2024. It selectively inhibits the menin–MLL interaction without compromising normal hematopoiesis. Integration, Not Isolation Small molecules are increasingly being used to enable and enhance other modalities: RNA therapeutics: Small molecules improve endosomal escape and stabilize formulations Cell therapy: Used to modulate immune responses or activate engineered switches Synthetic biology: Act as chemical triggers for gene circuits As Dr. Peter Tummino of Nimbus Therapeutics explains, “We apply our physics-based drug discovery engine to visualize small molecule–protein interactions with extraordinary detail… Combined with AI, we can design molecules with optimal drug-like properties with greater precision”. Case Studies: Innovation in Action KRAS G12D Inhibitor – Revolution Medicines: KRAS mutations were long considered “undruggable.” But RMC-9805, a covalent small molecule targeting KRAS G12D via a tricomplex glue mechanism, is changing that narrative. Alzheimer’s Disease – JNCASR, India: Researchers identified the miR-7a–Klf4 axis as a novel target for neuroinflammation and ferroptosis. Honokiol, a small molecule derived from Magnolia bark, showed promise in modulating this pathway and crossing the blood–brain barrier. AI-Driven Discovery – Schrödinger’s SGR-1505:Using computational chemistry, Schrödinger developed a potent MALT1 inhibitor for oncology, showcasing how AI and small molecules are converging to tackle complex targets. Voices from the Field “Rather than fade away, small molecules continue to be an important part of the industry’s therapeutic arsenal.” — Laura Howes, Chemical & Engineering News “New uses for small molecules are ones that were never considered 20 years ago and have redefined what chemists think of as druggable.” — Keith Hornberger, Arvinas “It’s not just a tool we use, but fundamental to our approach.” — Dr. Peter Tummino, Nimbus Therapeutics Final Takeaway Small molecules are not relics—they’re refined instruments. Their adaptability, accessibility, and deep mechanistic understanding make them foundational to both legacy and next-generation therapeutics. In a world of therapeutic complexity, small molecules offer elegant simplicity. And that, in itself, is a kind of power. Still small. Still mighty. And more essential than ever. References Frontiers in Drug Discovery Drug Hunter Case Studies Pharmaceutical Executive Interview with Dr. Tummino JNCASR Alzheimer’s Study Chemical & Engineering NewsBlog post description.