Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L

Parker, Erica N.; Odutola, Samuel O.; Wang, Yifan; Strecker, Tracy E.; Mukherjee, Rajeswari; Shi, Zhe; Chaplin, David J.; Trawick, Mary Lynn; Pinney, Kevin G.

doi:10.1016/j.bmcl.2016.12.039

Cited by 6 publications

(2 citation statements)

References 56 publications

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“…In follow up studies, Kishore et al and Parker et al further expanded the scope of thiosemicarbazone scaffold and developed diversely functionalized analogs that exhibited an enhanced inhibitory potency and promising cellular activities while still retaining the selectivity over cathepsin B [125,126]. In their latest study, Parker et al strategically transformed an active inhibitor with limited aqueous solubility into a water-soluble prodrug (Entry 23, Table 2), by phosphorylation of phenolic hydroxy group; this group was readily hydrolyzable by alkaline phosphatases, rendering the active pharmacophore [124]. The phosphate prodrug exhibited a remarkable 600-fold increase in solubility over the parent drug and did not disintegrate in aqueous solution, even after prolonged exposure at the physiological temperature.…”

Section: Thiosemicarbazonementioning

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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Section: Thiosemicarbazonementioning

confidence: 99%

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

Dana

Pathak

2020

Molecules

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“…Among these thirty six compounds, five were highly active against CathL (Song et al, 2013). Parker et al (2017) reported the KGP94, a member of the group of functionalized benzophenone thiosemicarbazone analogs, which showed similar inhibition capacity for CathL. However, this compound has low water dispersibility and to improve aqueous solubility, the phosphate prodrug, KGP420 can be used which converts to the parent compound, KGP94.…”

Section: Cathepsin L In Angiogenesismentioning

confidence: 99%

Status and Future Directions of Anti-metastatic Cancer Nanomedicines for the Inhibition of Cathepsin L

Tabish

Pranjol

Whatmore

et al. 2020

Front. Nanotechnol.

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Angiogenesis, tissue invasion and metastasis in the tumour microenvironment are all critical hallmarks of cancer. Upregulation of cathepsin L plays an important role in angiogenesis and metastasis through its ability to degrade the extracellular matrix, facilitating tissue remodeling and tumour cell invasion. Thus, cathepsin L is a potential therapeutic target for anticancer nanomedicine, with its inhibition emerging as an innovative and potentially promising therapeutic intervention for the development of anti-invasion and anti-metastatic enzyme therapies. Nanotechnology-based platforms have been extensively tested in the anti-cancer nanomedicine field with effective anti-tumour efficacy. These nanodrugs can suppress tumour cell proliferation, thereby reducing tumour growth. Recently, nanomedicinal approaches have also emerged as effective anti-metastatic strategies, including the use of graphene oxide and gold nanoparticles. With a focus on recent advances in developing nanotechnology to inhibit cathepsin L, this review provides an in-depth examination of this stimulating field in the context of tumour microenvironments. Innovative anti-metastatic agents may lead to new options for the treatment of cancers.

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Study on the Preparation and Antileukemic Activity of New Lipophilic 1-β-D-arabinofuranosylcytosine Derivatives

Chu

Tian

Hou

et al. 2018

J. Ocean Univ. China

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Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L

Cited by 6 publications

References 56 publications

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

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

Status and Future Directions of Anti-metastatic Cancer Nanomedicines for the Inhibition of Cathepsin L

Study on the Preparation and Antileukemic Activity of New Lipophilic 1-β-D-arabinofuranosylcytosine Derivatives

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