Human cathepsin D (CatD) is a pepsin-family aspartic protease, which is involved in many physiological and pathological processes in human. It is overexpressed in breast cancer cells and associated with tumor progression and metastasis. CatD inhibitors were proposed as potential cancer therapeutics and many compounds have been synthesized.
In this study, we report the development of macrocyclic inhibitors inspired by natural inhibitor of CatD, Pepstatin A. The cyclic scaffold was designed to mimic spatial conformation of the minimal pseudo-dipeptide binding motif, while removing unnecessary amino acids and replacing them with a suitable bridge connecting P2 and P3´ positions.
Reported compounds are composed of three sub-units linked together. The first sub-unit (2-hydroxy-3-amino acid) contains the transition state isostere (hydroxy group), which interacts with the active site aspartates. The second sub-unit contains R2 substituent filling the S2’ sub-site, while the third one is a linker connecting the first two units and interacting with the large hydrophobic S2-S3’ site of the enzyme binding cleft. Library of over 30 compounds was employed for scaffold optimization. Synthesis and inhibitory potency of these compounds with variable size of the bridge and various side chains in P1 and P2´ positions will be reported.