No abstract

The enzyme carboxypeptidase G2 (CPG2) is used in antibody-directed enzyme prodrug therapy (ADEPT) to catalyse the formation of an active drug from an inert prodrug. Free CPG2 in the bloodstream must be inhibited before administration of the prodrug in order to avoid a systemic reaction in the patient. Although a few small-molecule CPG2 inhibitors have been reported, none has been taken forward thus far. This lack of progress is due in part to a lack of structural understanding of the CPG2 active site as well as the absence of small molecules that can block the active site whilst targeting the complex for clearance. The work described here aimed to address both areas. We report the structural/functional impact of extensive point mutation across the putative CPG2 catalytic site and adjacent regions for the first time, revealing that residues outside the catalytic region (K208A, S210A and T357A) are crucial to enzyme activity. We also describe novel molecules that inhibit CPG2 whilst maintaining the accessibility of galactosylated moieties aimed at targeting the enzyme for clearance. This work acts as a platform for the future development of high-affinity CPG2 inhibitors that occupy new chemical space and will advance the safe application of ADEPT in cancer treatment.

The cover feature picture shows the binding of a new inhibitor to the CPG2 enzyme to prevent off‐site generation of an active drug as part of antibody‐directed enzyme prodrug therapy (ADEPT). ADEPT involves administration of an enzyme–antibody conjugate directed at tumor‐associated antigens, followed by administration of a prodrug that is enzymatically converted to its active form at the tumor site. This approach reduces the toxic effects of cancer therapy, but requires inhibition and clearance from circulation of any unbound conjugate ahead of administration of the prodrug. It is this goal that is the focus of the full paper by A. M. Dixon et al. on page 1959 in Issue 18, 2018 (DOI: 10.1002/cbic.201800186).