Suppressive effect of N-(benzyloxycarbonyl)-l-phenylalanyl-l-tyrosinal on bone resorption in vitro and in vivo

Woo, Je‐Tae; Yamaguchi, Kohji; Hayama, Takahiro; Kobori, Takeo; Sigeizumi, Sanae; Sugimoto, Kikuo; Kondô, Kiyosi; Tsuji, Tomoko; Ohba, Yasuo; Tagami, Kahori; Sumitani, Koji

doi:10.1016/0014-2999(95)00858-6

Cited by 32 publications

(19 citation statements)

References 20 publications

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“…44 Pharmacological intervention of CTSL also yielded similar suppression of bone resorption in osteoporotic mice. 45 In addition to the anticipated decline in bone resorption, KGP94 also led to a drastic impairment of the osteoclast formation process (Fig. 4).…”

Section: Discussionmentioning

confidence: 91%

Cathepsin L inactivation leads to multimodal inhibition of prostate cancer cell dissemination in a preclinical bone metastasis model

Sudhan

Pampo

Rice

et al. 2016

Intl Journal of Cancer

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It is estimated that approximately 90% of patients with advanced prostate cancer develop bone metastases; an occurrence that results in a substantial reduction in the quality of life and a drastic worsening of prognosis. The development of novel therapeutic strategies that impair the metastatic process and associated skeletal adversities is therefore critical to improving prostate cancer patient survival. Recognition of the importance of Cathepsin L (CTSL) to metastatic dissemination of cancer cells has led to the development of several CTSL inhibition strategies. The present investigation employed intra-cardiac injection of human PC-3ML prostate cancer cells into nude mice to examine tumor cell dissemination in a preclinical bone metastasis model. CTSL knockdown confirmed the validity of targeting this protease and subsequent intervention studies with the small molecule CTSL inhibitor KGP94 resulted in a significant reduction in metastatic tumor burden in the bone and an improvement in overall survival. CTSL inhibition by KGP94 also led to a significant impairment of tumor initiated angiogenesis. Furthermore, KGP94 treatment decreased osteoclast formation and bone resorptive function, thus, perturbing the reciprocal interactions between tumor cells and osteoclasts within the bone microenvironment which typically result in bone loss and aggressive growth of metastases. These functional effects were accompanied by a significant downregulation of NFκB signaling activity and expression of osteoclastogenesis related NFκB target genes. Collectively, these data indicate that the CTSL inhibitor KGP94 has the potential to alleviate metastatic disease progression and associated skeletal morbidities and hence may have utility in the treatment of advanced prostate cancer patients.

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Section: Discussionmentioning

confidence: 91%

Cathepsin L inactivation leads to multimodal inhibition of prostate cancer cell dissemination in a preclinical bone metastasis model

Sudhan

Pampo

Rice

et al. 2016

Intl Journal of Cancer

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“…The most potent cathepsin L inhibitor of this series was Z-Phe-Phe-H (IC 50 = 0.74 nM) ( Figure 12b) that showed more than 90-fold selectivity over cathepsin B. Interestingly; their data demonstrated the importance of aromatic amino acids, such as phenylalanine and tyrosine, at the P1 position in determining the potency and selectivity towards cathepsin L; O-alkylation of tyrosine group diminishes the inhibitory efficiency as in Z-Phe-Tyr(Bu)-H (IC 50 : 6.96 nM). In a follow-up publication, they further tested the efficacy of Z-Phe-Tyr-H (IC 50 : 0.85 nM, 100-fold selective over cathepsin B) (Figure 12b) in vitro and in vivo [140]. This compound effectively inhibited parathyroid hormone-stimulated osteoclastic bone resorption in pit formation assays, and suppressed bone weight loss of ovariectomized mouse in a dose-dependent manner when administered intraperitoneally.…”

Section: Peptidyl Aldehydesmentioning

confidence: 99%

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

Dana

Pathak

2020

Molecules

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Human cathepsin L belongs to the cathepsin family of proteolytic enzymes with primarily an endopeptidase activity. Although its primary functions were originally thought to be only of a housekeeping enzyme that degraded intracellular and endocytosed proteins in lysosome, numerous recent studies suggest that it plays many critical and specific roles in diverse cellular settings. Not surprisingly, the dysregulated function of cathepsin L has manifested itself in several human diseases, making it an attractive target for drug development. Unfortunately, several redundant and isoform-specific functions have recently emerged, adding complexities to the drug discovery process. To address this, a series of chemical biology tools have been developed that helped define cathepsin L biology with exquisite precision in specific cellular contexts. This review elaborates on the recently developed small molecule inhibitors and probes of human cathepsin L, outlining their mechanisms of action, and describing their potential utilities in dissecting unknown function.Molecules 2020, 25, 698 2 of 41 also now well established and has been a subject of elegant reviews elsewhere [25][26][27]. Unfortunately, several overlapping and redundant functions of cathepsin L have also emerged [5,[28][29][30]. It is therefore critically important that its functional biology in both normal and disease-specific cell types be clearly annotated before significant resources are directed in drug discovery endeavors. In this review, we will briefly outline the biogenesis of cathepsin L, describe its post-translational processing and trafficking, and highlight key structural features required for formation of an active and mature cathepsin L. A brief summary of cathepsin L biology and its role in human diseases is provided next. Finally, a detailed and up-to-date report on existing cathepsin L-targeting small molecule inhibitors and functional probes with their mechanistic details is described.Human cathepsin L gene, CTHL (Uniprot primary accession number: P07711), located at the 9q21-q22 position of chromosome 9, encodes for a total of 333 amino acid peptide sequence (M.W. = 37,564 kDa) [31]. The coding space includes the regions of a N-terminal signal peptide, two pro-peptides, and two mature peptides comprising of a heavy (H) chain and a light (L) chain ( Figure 1). After transcription, the signal peptide is co-translationally removed in polysome and the resulting 41 kDa pro-cathepsin L is translocated to endoplasmic reticulum where it undergoes N-linked glycosylation with mannose rich sugars. The mannose sugars on the pro-cathepsin L are then phosphorylated in cis Golgi by UDP-N-acetylglucosamine:N-acetylglucosaminephosphotransferase enzyme [32]. The mannose-6-phosphate (M6P) receptors located on the surface of the trans Golgi network recognize the M6P-pro-cathepsin peptide and deliver the pro-cathepsin L peptide to the lysosome via the endolysosomal pathway. The weakly acidic environment of endosome/lysosome releases M6P receptors and the phosphate ...

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“…Whereas Z-FY-CHO specifically inhibits cathepsin L [31], CA-074 Me, although initially introduced as a cathepsin B-specific inhibitor, shows overlapping effects on cathepsin B and L if applied to living cells [32]. Both inhibitors were found to be equally effective as leupeptin and E-64 in preventing DIRC2 proteolysis ( Figures 6A and 6B), strongly suggesting a critical involvement of cathepsin L. However, based on the experimental data described, an additional role for cathepsin B cannot fully be excluded owing to the overlapping specificities of the inhibitors used.…”

Section: Inhibitory Profiling Indicates the Involvement Of Lysosomal mentioning

confidence: 99%

Disrupted in renal carcinoma 2 (DIRC2), a novel transporter of the lysosomal membrane, is proteolytically processed by cathepsin L

Savalas

Gasnier

Damme

et al. 2011

Biochemical Journal

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DIRC2 (Disrupted in renal carcinoma 2) has been initially identified as a breakpoint-spanning gene in a chromosomal translocation putatively associated with the development of renal cancer. The DIRC2 protein belongs to the MFS (major facilitator superfamily) and has been previously detected by organellar proteomics as a tentative constituent of lysosomal membranes. In the present study, lysosomal residence of overexpressed as well as endogenous DIRC2 was shown by several approaches. DIRC2 is proteolytically processed into a N-glycosylated N-terminal and a non-glycosylated C-terminal fragment respectively. Proteolytic cleavage occurs in lysosomal compartments and critically depends on the activity of cathepsin L which was found to be indispensable for this process in murine embryonic fibroblasts. The cleavage site within DIRC2 was mapped between amino acid residues 214 and 261 using internal epitope tags, and is presumably located within the tentative fifth intralysosomal loop, assuming the typical MFS topology. Lysosomal targeting of DIRC2 was demonstrated to be mediated by a N-terminal dileucine motif. By disrupting this motif, DIRC2 can be redirected to the plasma membrane. Finally, in a whole-cell electrophysiological assay based on heterologous expression of the targeting mutant at the plasma membrane of Xenopus oocytes, the application of a complex metabolic mixture evokes an outward current associated with the surface expression of full-length DIRC2. Taken together, these data strongly support the idea that DIRC2 is an electrogenic lysosomal metabolite transporter which is subjected to and presumably modulated by limited proteolytic processing.

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Suppressive effect of N-(benzyloxycarbonyl)-l-phenylalanyl-l-tyrosinal on bone resorption in vitro and in vivo

Cited by 32 publications

References 20 publications

Cathepsin L inactivation leads to multimodal inhibition of prostate cancer cell dissemination in a preclinical bone metastasis model

Cathepsin L inactivation leads to multimodal inhibition of prostate cancer cell dissemination in a preclinical bone metastasis model

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

Disrupted in renal carcinoma 2 (DIRC2), a novel transporter of the lysosomal membrane, is proteolytically processed by cathepsin L

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