Discovery of novel cathepsin inhibitors with potent anti-metastatic effects in breast cancer cells

Liu, Yuan; Sheng, Lei; He, Wenhui; Zou, Chunyang; Hu, Baichun; Liu, Jun; Ge, Wentao; Liu, Yang; Wang, Jian; Ma, Enlong

doi:10.1016/j.bioorg.2018.09.029

Cited by 17 publications

(9 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, asperphenidine F1, was the only active candidate against the pancreas cell line, suggesting the nicotinic acid analogs being more active than the benzoic acid analogs. Although our cytotoxicity results for asperphenamates F and Y, as well as asperphenidine F1 are comparable to the previously published data, none of them show improved bioactivity compared to synthetic asperphenamate derivatives (Li et al, 2012;Yuan et al, 2012Yuan et al, , 2018Yuan et al, , 2019Yuan et al, , 2020Liu et al, 2016Liu et al, , 2018.…”

Section: Discussionsupporting

confidence: 85%

“…Additionally, the compound has also been isolated in trace amounts from a number of unrelated plant species (Wu et al, 2004;Dang et al, 2014;Zhou et al, 2017;Bunteang et al, 2018;Caridade et al, 2018), suggesting endophytic fungi being the actual producers, rather than the plants. Although asperphenamate is mainly known for its antitumour activity and immense synthetic chemists interest in asperphenamate backbone modification (Li et al, 2012;Yuan et al, 2012Yuan et al, , 2018Yuan et al, , 2019Yuan et al, , 2020Liu et al, 2016), recent studies have also shown asperphenamate to be a potential neuroinflamatory inhibitor (Zhou et al, 2017), and to possess anti-HIV (Bunteang et al, 2018) and antidiabetic (Del Valle et al, 2016) properties. In recent years, a handful of new natural analogs have been isolated, namely Asperphenamates B (4) and C (5) (Liu et al, 2018), and 4-OMe-asperphenamate (Zheng et al, 2013;Ratnaweera et al, 2016) (6) from filamentous fungi.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mass Spectrometry Guided Discovery and Design of Novel Asperphenamate Analogs From Penicillium astrolabium Reveals an Extraordinary NRPS Flexibility

et al. 2021

View full text Add to dashboard Cite

Asperphenamate is a small peptide natural product that has gained much interest due to its antitumor activity. In the recent years numerous bioactive synthetic asperphenamate analogs have been reported, whereas only a handful of natural analogs either of microbial or plant origin has been discovered. Herein we describe a UHPLC-HRMS/MS and amino acid supplement approach for discovery and design of novel asperphenamate analogs. Chemical analysis of Penicillium astrolabium, a prolific producer of asperphenamate, revealed three previously described and two novel asperphenamate analogs produced in significant amounts, suggesting a potential for biosynthesis of further asperphenamate analogs by varying the amino acid availability. Subsequent growth on proteogenic and non-proteogenic amino acid enriched media, revealed a series of novel asperphenamate analogs, including single or double amino acid exchange, as well as benzoic acid exchange for nicotinic acid, with the latter observed from a natural source for the first time. In total, 22 new asperphenamate analogs were characterized by HRMS/MS, with one additionally confirmed by isolation and NMR structure elucidation. This study indicates an extraordinary nonribosomal peptide synthetase (NRPS) flexibility based on substrate availability, and therefore the potential for manipulating and designing novel peptide natural products in filamentous fungi.

show abstract

Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Mass Spectrometry Guided Discovery and Design of Novel Asperphenamate Analogs From Penicillium astrolabium Reveals an Extraordinary NRPS Flexibility

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The recent focus on target-and ligand-binding drug design to selectively inhibit specific CTSs has provided excellent results in overcoming such issue [19,72,[204][205][206][214][215][216][217][218][219][220][221][222]. In this context, several new strategies have been reported for successfully CTS targeting, including designed ankyrin repeat proteins (DARPins) with high CTSB blocking activity [222], non-peptide synthetic molecules with anti-CTSK [71] and anti-CTSD [223] activity, and naturally occurring asperphenamate [224]. Natural depsipeptides inhibitor of CTSD, namely izenamides A, B, and C, have been recently successfully tested [225], and quantum mechanics/molecular modeling studies of the mechanism of cysteine protease inhibition by dipeptidyl nitroalkenes provided promising results [226].…”

Section: Cathepsin Inhibitors and Their Therapeutic Applicationsmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

View full text Add to dashboard Cite

Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

show abstract

“…Thus, simultaneously highlighting the importance of lysosomal cathepsin D inhibition in sensitizing resistant cells to therapy [88,89,90,91]. Furthermore, Yuan et al (2018) explored naturally occurring products towards cathepsins -L and -S inhibition and found a compound that worked to varying (yet promising) degrees with an IC 50 as low as 13.12 μM in the inhibition of BC metastasis [92].…”

Section: Cathepsin-derived and -Targeted Therapeuticsmentioning

confidence: 99%

Cysteine Cathepsin Protease Inhibition: An update on its Diagnostic, Prognostic and Therapeutic Potential in Cancer

et al. 2019

View full text Add to dashboard Cite

In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic research in this area in a translational direction; recent findings have given rise to a number of exciting developments in the areas of cancer diagnosis; prognosis and therapeutic development. As a fast-moving area of research; the focus of this review brings together the latest findings and highlights the translational significance of these developments.

show abstract

Discovery of novel cathepsin inhibitors with potent anti-metastatic effects in breast cancer cells

Cited by 17 publications

References 22 publications

Mass Spectrometry Guided Discovery and Design of Novel Asperphenamate Analogs From Penicillium astrolabium Reveals an Extraordinary NRPS Flexibility

Mass Spectrometry Guided Discovery and Design of Novel Asperphenamate Analogs From Penicillium astrolabium Reveals an Extraordinary NRPS Flexibility

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Cysteine Cathepsin Protease Inhibition: An update on its Diagnostic, Prognostic and Therapeutic Potential in Cancer

Contact Info

Product

Resources

About