REACHING “UNDRUGGABLE” TARGETS

Most medicines today fall into one of two categories: small molecules or biologics. Both types have inherent limitations. Macrocycles occupy a middle ground between the two, giving them the potential to combine the best attributes of each while overcoming their shortcomings.

Small molecule medications are well-structured, stable, can often be taken orally, and are relatively easy and inexpensive to make. However, they can usually only address disease targets that have appropriate pockets on their surface into which small molecules can bind. These binding pockets provide several points of contact between the small molecule drug and the target protein, allowing the drug to modify the function of the protein. But small molecule medications cannot easily disrupt protein-to-protein interactions implicated in many diseases because these protein-to-protein interactions often do not have suitable deep pockets for small molecule medications to bind.

Biologics, such as antibodies, on the other hand, are significantly larger and can provide exquisite selectivity and potency against a target, including protein-protein interactions.

However, they are unable to cross cell membranes and so cannot be absorbed if swallowed and must be injected. Further, their inability to cross membranes means that they cannot access protein-protein interactions that are inside cells. Intracellular protein-protein interactions are central to many disease processes, including many cancers and inflammatory diseases.

Thus, a vast number of therapeutic targets are beyond the reach of these two conventional drug classes. Scientists call these hard-to-reach human proteins “undruggable targets.”