Inhibitors of Cathepsin B

Abstract

Cathepsin B is an abundant and ubiquitously expressed cysteine peptidase of the papain family. It is involved in many physiological processes, such as remodeling of the extracellular matrix (wound healing), apoptosis, and activation of thyroxine and renin. In addition to its physiological roles, cathepsin B is important in many pathological processes, such as inflammation, parasite infection and cancer, where it is highly up-regulated. In cancer patients, elevated cathepsin B activity correlates to poor therapy outcome. Therefore, it is not surprising that the use of cathepsin B inhibitors reduces both tumor cell motility and invasiveness in vitro. This review summarizes recent developments in cathepsin B inhibition. To date, numerous protein inhibitors of cathepsin B have been described, some of which are of endogenous origin and function as regulators of cathepsin B activity in the cell, such as the cystatins. In addition, some exogenous protein inhibitors of cathepsin B have been isolated from various natural sources, and the use of X-ray crystal structures of cathepsin B complexed with such protein inhibitors has resulted in the design and synthesis of many new small-molecular-weight compounds as inhibitors of cathepsin B. These synthetic compounds generally contain an electrophilic functionality that reacts with cathepsin B. In the present review, these inhibitors are divided according to their mechanisms of action, as reversible and irreversible, and then further subdivided into groups for their full descriptions.

Design, synthesis and characterisation of new chimeric ruthenium(ii)–gold(i) complexes as improved cytotoxic agents

“…35 Cat B has been proposed as a possible therapeutic target for the control of tumor progression. 36 Indeed, RAPTA Ru compounds which inhibit cat B with IC50 values in the low micromolar range effectively reduce the mass and the number of metastases in vivo . 37 We therefore, studied the inhibition of Cat B by compounds 1, 3 and by ruthenium [Ru( p -cymene)Cl 2 (η 1 -dppm)] (see experimental section for details and IC50 values in Table 3).…”

Droplet Electrospray Ionization Mass Spectrometry for High Throughput Screening for Enzyme Inhibitors

“…Among them, 3 contain known “warheads” of small molecule cathepsin B inhibitors (cefmetazole and cefaclor are β-lactams and alexidine contains a biguanide 32 ). The remaining 11 hits do not contain structural motifs established as cathepsin B inhibitors, suggesting an opportunity to develop modulators based on novel moieties.…”

“…Successful inhibitors include epoxysuccinyl, aziridinyl, biguanide, and β-lactam derivatives. 31,32 The MS screen used here reveals several potential new inhibitors.…”

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

“…Therefore, it is necessary to develop CTSB inhibitors, and some of them (cyctatins, CA-074, etc.) are able to reduce cancer cell motility and invasiveness 58 , 59 . Similarly, CTSD can act as a mitogen on both cancer and stromal cells to stimulate their proinvasive and prometastatic properties 57 .…”