Small-molecule inhibitor: PD150606

Name

Peptidases inhibited: PD150606 is a very specific inhibitor of calpains (family C2) in preference to other cysteine peptidases (Wang et al., 1996). Calpains reported to be inhibited include calpain-1: K_i 0.21x10^-6 M) and calpain-2: K_i 0.37x10^-6 M).
Mechanism: Inhibition is reversible and uncompetitive with respect to substrate; it is evidently not active-site-directed, since PD150606 does not protect calpain from inactivation by E64 (Wang et al., 1996). Crystal structures of calpain-PD150606 complexes have been described by Lin et al. (1997) (who consider the mechanism of inhibition) and by Todd et al. (2003). It is likely that binding of the inhibitor to the calcium-binding sites disrupts the conformational changes that are necessary to activate the catalytic domain (Wang et al., 1996).
Pharmaceutical relevance: A cell-permeant inhibitor that has been evaluated for protection against neuronal cell death (Wang et al., 1996).

CID at PubChem: 444306
Structure
Chemical/biochemical name: 3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid
Formula weight: 308
Related inhibitors: PD151746 is another 2-mercapto-propenoic acid inhibitor of calpains.

Comment: PD150606 has been used in a number of studies of calpain functions in living systems. Other compounds based on alpha-mercaptoacrylic acid also inhibit, and the unsaturated bond is essential (Wang et al., 1996).
Reviews: Wang et al. (1996)