Strategy in inhibition of cathepsin B, a target in tumor invasion and metastasis

In Taek Lim, Samy Meroueh, Mijoon Lee, Mary Jane Heeg, Shahriar Mobashery

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)10271-10277
Number of pages7
JournalJournal of the American Chemical Society
Volume126
Issue number33
DOIs
StatePublished - Aug 25 2004
Externally publishedYes

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Cathepsin B
Tumors
Neoplasm Metastasis
Neoplasms
Cysteine Proteinase Inhibitors
Cysteine Proteases
Carboxylic Acids
Carboxylic acids
Kinetic parameters
Antineoplastic Agents
Libraries
Cathepsins
Catalytic Domain
Esters
Enzymes
Molecules

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Strategy in inhibition of cathepsin B, a target in tumor invasion and metastasis. / Lim, In Taek; Meroueh, Samy; Lee, Mijoon; Heeg, Mary Jane; Mobashery, Shahriar.

In: Journal of the American Chemical Society, Vol. 126, No. 33, 25.08.2004, p. 10271-10277.

Research output: Contribution to journalArticle

Lim, In Taek ; Meroueh, Samy ; Lee, Mijoon ; Heeg, Mary Jane ; Mobashery, Shahriar. / Strategy in inhibition of cathepsin B, a target in tumor invasion and metastasis. In: Journal of the American Chemical Society. 2004 ; Vol. 126, No. 33. pp. 10271-10277.
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