Many drugs in cancer therapy are generally toxic for cells. They still work, but they do rely on the fact that they kill cancer cells more quickly than healthy cells, often only based their rapid cell division rate. As a side effect, otherhealthy cells with similar properties are targeted too—and this is the reason why hair loss is such a typical symptom for cancer patients.

Antibody-drug conjugates (ADCs) usually combine the strong selectivity of an antibody with a strong cytotoxin. The idea is that the antibody accumulates at cancerous cells due to the recognition motif (for example, the antibody targets the cell-surface receptor HER2 which is overexpressed in some cancers), and the general environment leads to the release of the conjugated warhead (the cytotoxin, often MMAE is used). This leads to a generally better side effect profile, as the cytoxic effect is limited to the area of where the cancer is. However, antibodies are expensive and the precise conjugation and the ideal linker between the antibody and the warhead are still subject of ongoing research (but many ADCs are clinically approved!). So the idea of the study from Matthias was: Why not trying to achieve the selectivity with only small molecules?

EGFR is a growth factor overexpressed in some cancer cells, just like the HER2 receptor. There are drugs available that target EGFR selectively and are covalent such as afatinib. Matthias synthesised an afatinib analogue having a tetrazine pointing outside of the binding pocket. Cells are incubated with this conjugate over a time, essentially modifying all EGFR proteins with this tetrazine functional group. Then, he adds a caged variant of MMAE (caged means ‘not as toxic’ as the uncaged variant). As a cage, he uses a trans-cyclooctene. Both the tetrazine and the trans-cyclooctene react together in a inverse electron-demand Diels-Alder reaction (IEDDA), a typical ‘click’ reaction that is reasonable fast and selective reaction. This IEDDA is even irreversible, as nitrogen is released. The reaction causes the uncaging of the MMAE which is then free to float around the cell to kill it.

The paper compares MMAE with doxorubicin and why the former is a better candidate then the latter despite the larger toxicity of the caged MMAE. The very descriptive comic drawings helps to understand the paper while the science is solid.

The paper was published online on the 15th of January 2026 in RCS Medicinal Chemistry and is Open Access.