Small-molecule inhibitor: bestatin

Name

History: Bestatin was first described as an inhibitor of aminopeptidase B (M01.014) produced by actinomycetes (Umezawa et al., 1976)).
Peptidases inhibited: Inhibits a range of metallo-aminopeptidases in several families and clans. Inhibition of aminopeptidase B is particularly potent, with nanomolar K_i values (Ocain & Rich, 1988). Aminopeptidase N, leukotriene A4 hydrolase and leucyl aminopeptidase are much more weakly inhibited (Ocain & Rich, 1988; Muskardin et al., 1994; Taylor et al., 1993). The bacterial aminopeptidase Ap1 is potently inhibited (Wilkes & Prescott, 1985).
Mechanism: Slow, tight-binding, reversible inhibition. Structures of complexes have been resolved for leukotriene A4 hydrolase (Thunnissen et al., 2001), leucyl aminopeptidase (Kim et al., 1993) and aminopeptidase Ap1 (Stamper et al., 2004).
Pharmaceutical relevance: Bestatin has low toxicity and has been evaluated for the treatment of cancers (Imamura & Kimura, 2000; Ichinose et al., 2003; Aozuka et al., 2004).
DrugBank: DB03424

CID at PubChem: 72172
ChEBI: 598867
Structure
Chemical/biochemical name: 2-(3-amino-2-hydroxy-4-phenyl-butanoyl)amino-4-methyl-pentanoic acid
Related inhibitors: Sulfur-containing analogues of bestatin (Ocain & Rich, 1988). Azidobestatin (Taylor et al., 1992). Bestatin analogue from Streptomyces neyagawaensis SL-387 (Chung et al., 1996). Nitrobestatin (Nankya-Kitaka et al., 1998).

Reviews: Powers & Harper (1986); Stamper et al. (2004); Aozuka et al., 2004