Small molecule drug

A small molecule is a drug built by chemical synthesis rather than grown in living cells. Its molecules are hundreds of times lighter than an antibody, which lets them cross cell membranes and reach targets inside the cell, such as kinases, DNA repair enzymes and survival proteins. Most kinase inhibitors, PARP inhibitors, BCL2 inhibitors and hormone blockers are small molecules, and so is almost every classic chemotherapy drug.

Because they are stable and absorbed from the gut, small molecules are usually tablets or capsules taken at home, which is why so much of modern targeted therapy is oral. The trade-offs are the flip side of the same chemistry: they are cleared by liver enzymes, so food and other medicines can change their levels; they can bind related proteins and cause off-target side effects; and a single mutation in the target can stop them binding, which is a common route to resistance.

The other big class is biologics: antibodies, antibody-drug conjugates, bispecifics and cell therapies. These are made in cells, given by infusion or injection, and act mainly on targets at the cell surface or in the blood. Many treatment plans combine both, for example a small-molecule inhibitor with an antibody, or chemotherapy with a checkpoint inhibitor. The rule-of-thumb properties that predict whether a small molecule will be absorbed by mouth were set out by Lipinski and by Veber, and still guide drug design.