Enhancing the Drug-Like Profile of a Potent Peptide PACE4 Inhibitor by the Formation of a Host–Guest Inclusion Complex with β-Cyclodextrin

The enzyme PACE4 has been validated as a promising therapeutic target to expand the range of prostate cancer (PCa) treatments. In recent years, we have developed a potent peptidomimetic inhibitor, namely, compound C23 (Ac-(DLeu)LLLRVK-4-amidinobenzylamide). Like many peptides, C23 suffers from an unfavorable drug-like profile which, despite our efforts, has not yet benefited from the usual SAR studies. Hence, we turned our attention toward a novel formulation strategy, i.e., the use of cyclodextrins (CDs). CDs can benefit compounds through the formation of "host-guest" complexes, shielding the guest from degradation and enhancing biological survival. In this study, a series of βCD-C23 complexes have been generated and their properties evaluated, including potency toward the enzyme in vitro, a cell-based proliferation assay, and stability in plasma. As a result, a new βCD-formulated lead compound has been identified, which, in addition to being more soluble and more potent, also showed an improved stability profile.