Foo, K., Ethirajulu, K., & Xu, W. (2026). Macrocycles: On the Rise for Bridging Small Molecules and Biologics. Journal of Medicinal Chemistry, 69(3), 1783–1785. https://doi.org/10.1021/acs.jmedchem.6c00061
Abstract:
Over the last decade, drug discovery has evolved from the era of traditional small molecules toward large biologics. Although FDA approvals have been consistently dominated by small molecules, partly due to synthetic tractability and favourable pharmacokinetic profiles of drug-like compounds, the growing interest in large molecules, such as biologics and monoclonal antibodies, is evident from the market profile. In view of a small fraction of the human proteome is truly druggable by conventional drug-like therapeutic modalities, the chase in large molecules from pharma’s interest is on the rise, driven largely by the FDA approval of ADCs and the emergence of bi-specific antibodies. Although small molecules owe their advantage in oral bioavailability and cost-effectiveness, their limitation to modulate complexes featuring flat protein–protein interfaces have left many targets unexplored. While biologics have experienced significant attention and expansion to extracellular and secreted targets, challenges remain in tissue penetration, oral delivery, and manufacturing complexity. In addition, the high cost for production and immunogenic nature of biologics warrants the need for additional therapeutics to fill the gap.1 Bridging these two territories, macrocycles represent an exciting frontier poised to fill the gaps, unlocking new therapeutic opportunities across a wider biological landscape.
License type:
Publisher Copyright
Funding Info:
This research is supported by core funding from: Experimental Drug Development Centre (EDDC)
Grant Reference no. : Core