Exploration of calpain inhibitors incorporating constrained residues at P2 position and their potential as anti-tumor agents

Calpain is a nonlysosomal calcium-activated intracellular neutral cysteine protease. The two major isoforms of calpain universally distributed in most mammalian tissues are calpain I and calpain II. Calpain is implicated in a variety of biological roles including signal transduction, cell cycle, apoptosis and long-term potentiation however, the exact physiological role of calpain is yet to be determined. The role of calpains has been linked to different pathologies such as stroke, cardiac ischaemia, muscular dystrophy, cataract and Alzheimer's disease. Calpain inhibitors are therefore of interest as therapeutic agents and as biomedical tools.Several isolated natural products, peptide-based synthetic and semi-synthetic inhibitors have been reported as calpain inhibitors. Unfortunately, most of the inhibitors show poor cell permeability, metabolic stability and calpain selectivity, which makes it difficult to understand calpain activity in vivo.As part of our efforts to develop novel calpain inhibitors we synthesized compounds incorporating constrained residues at P2-position. We also explored the P3-position of calpain inhibitors with different aliphatic and aromatic substituents. Ki values for calpain inhibition were in the low micro molar range.Calpains have recently been suggested as novel molecular targets for cancer therapy. We have tested the anti-proliferative activity of aldehyde calpain inhibitors in cancer and non-cancer cell lines. Potent anti-proliferative compounds with IC50's in the low micromolar range with promising anti-leukemic activity have been identified.