Strategy in Inhibition of Cathepsin B, A Target in Tumor Invasion and Metastasis

Abstract

Cathepsin B, a cysteine protease, is an important target in fighting cancer. This enzyme has been implicated in enhancing tumor invasiveness and metastasis, therefore inhibitors for cathepsin B are highly sought as potential anticancer and antimetastatic agents. A structure-based design effort was pursued in arriving at a template for inhibition of cathepsin B. Focused compound libraries were synthesized based on this template, which were screened for cathepsin B inhibitory properties. Compound 2, 1-(2(R)-[1(S)-acetoxy-2-[2(S)-(2,4-difluoro-benzoylamino)-3-phenyl-propionylaminooxy]-2-oxo-ethyl]-pentanoyl)-pyrrolidine-2(S)-carboxylic acid benzyl ester, is the prototype of this novel class of cysteine protease inhibitor that emerged from the search. The molecule modifies the active site of cathepsin B covalently, irreversibly, and efficiently, a process for which the kinetic parameters were evaluated. A set of three judiciously altered variants of compound 2 was also synthesized to explore the details of the proposed mechanism of action by this inhibitor. Compound 2 and its analogues may prove useful tools in reversing the deleterious effect of cathepsin B in fighting cancer.

The Occluding Loop of Cathepsin B Prevents Its Effective Inhibition by Human Kininogens

“…48 The importance of cathepsin B as drug target in human illness, including tumor metastasis, inflammation, or Alzheimer disease, 19 requires an improved understanding of cathepsin B regulation, which can be exploited in the design of more selective and potent inhibitors. 53 The absence of robust interactions between cathepsin B and kininogens that favor the CP/CPI imbalance and the deleterious activity of cathepsin B is of significant interest. The rationale for the present work was to account for the ineffective inhibition of cathepsin B by kininogens.…”

Subcloning and Expression of Functional Human Cathepsin B and K in E. coli: Characterization and Inhibition by Flavonoids

“…It has been implicated in a variety of diseases including cancer invasion and metastasis (Ledakis et al, 1996;Matarrese et al, 2010;Roshy et al, 2003;Sinha et al, 2001;Szpaderska and Frankfater, 2001;Yan et al, 1998), angiogenesis (Im et al, 2005;Kruszewski et al, 2004;Malla et al, 2011;Sinha et al, 1995), inflammation (Hashimoto et al, 2001;Kakegawa et al, 2004), and Alzheimer's Disease (Gan et al, 2004;Hook, 2006;Hook et al, 2008). Thus, cathepsin B is a promising target for anti-cancer drug design (Lim et al, 2004;Palermo and Joyce, 2008) and a potential target for Alzheimer's Disease (Hook et al, 2008 (Lecaille et al, 2008). Cathepsin K is highly expressed in osteoclasts (Drake et al, 1996) but also occurs in lung epithelia cells (Bühling et al, 1999), cultured primary neonatal skin fibroblasts activated chondrocytes, and in synovial fibroblasts of patients suffering from rheumatoid arthritis (Lecaille et al, 2008;Ruettger et al, 2008;Skoumal et al, 2005).…”

Fluorobenzoyl dipeptidyl derivatives as inhibitors of the Fasciola hepatica cysteine protease cathepsin L1

“…The initial series of compounds synthesized concentrated on modification of the P1 position, with benzyl ester protection of the C-terminus (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). At this position, the methylene unit of the C-terminal amino acid glycine was increased in length.…”

“…Previous work in these laboratories has identified N-benzoyl-dipeptidyl derivatives as potential inhibitors of the Fasciola hepatica protease, such as N-benzoyl-L-leucine-glycine 37 (IC 50 = 10.0 µM) and Ncinnamoyl-L-leucine-glycine nitrile 38 (IC 50 = 11.0 µM) 10 . The fluorobenzoyl moiety has been shown to be an effective N-terminal substituent in various potent inhibitors 11 . …”