First targeted protein degrader begins phase I clinical trial

Despite the fact that less than 20% of the proteome has enzymatic activity, most drug development efforts have so far focused on identifying enzymatic inhibitors. However, targeting a cell’s proteasomal machinery is now considered an effective area of research. As reported in Nature Reviews, the first protein degrader has reached a phase I clinical trial for patients with prostate cancer.

Traditional inhibitors require more drug than there is target. Instead, the new chemical entities that the researchers have developed can allow very low and less frequent dosing, consequently improving the safety margin. The new therapeutic aims to dissociate pharmacodynamics from pharmacokinetics, producing a short-lived protein degrader that elicits a long-lasting effect on the target.

At IRBM, we have extensive expertise in the synthesis and characterization of ADME properties of new molecules that do not align with Lipinski’s Rule of Five. We have developed novel approaches that evaluate the permeability and metabolism of these new therapeutics. Moreover, we have the capability to identify new peptide binders for specific E3 ligases – an essential component of a targeted protein degrader.