Antitumor activity and structure-activity relationship of heparanase inhibitors: Recent advances

Fu, Kaishuo; Bai, Zhifeng; Chen, Lanlan; Ye, Wenchong; Wang, Meizhu; Hu, Jiliang; Liu, Chunhui; Zhou, Wen

doi:10.1016/j.ejmech.2020.112221

Cited by 5 publications

(2 citation statements)

References 139 publications

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“…In fact, muparfostat, and heparin derivatives roneparstat and necuparanib are heterogeneous mixtures which could limit product characterisation and standardisation, and all these clinical candidates need to be administered by a parenteral route. Small-molecule heparanase inhibitors could be, in principle, more manageable and suitable for oral administration, and some of them have been prepared and evaluated at preclinical stages, 4 , 9 , 14 as the 1,3-diphenylurea 1 15 , the 2-aryl-benzimidazole 2 16 , the benzoxazol-5-yl-acetic acid 3 17 and the acidic phthalimide OGT2492 ( 4 ) 18 in Figure 1 . Despite the promising initial characterisation, no small-molecule inhibitor was further advanced to clinical trials.…”

Section: Introductionmentioning

confidence: 99%

New classes of potent heparanase inhibitors from ligand-based virtual screening

Pala

Scalvini

Elisi

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Heparanase is a validated target in cancer therapy and a potential target for several inflammatory pathologies. A ligand-based virtual screening of commercial libraries was performed to expand the chemical space of small-molecule inhibitors. The screening was based on similarity with known inhibitors and was performed in several runs, starting from literature compounds and progressing through newly discovered inhibitors. Among the fifty-five tested compounds, nineteen had IC 50 values lower than 5 mM and some showed remarkable potencies. Importantly, tere-and isophthalamides derivatives belong to new structural classes of heparanase inhibitors and some of them showed enzyme affinities (61 and 63, IC 50 ¼ 0.32 and 0.12 mM, respectively) similar to those of the most potent small-molecule inhibitors reported so far. Docking studies provided a comprehensive binding hypothesis shared by compounds with significant structural diversity. The most potent inhibitors reduced cell invasiveness and inhibited the expression of proangiogenic factors in tumour cell lines.

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Section: Introductionmentioning

confidence: 99%

New classes of potent heparanase inhibitors from ligand-based virtual screening

Pala

Scalvini

Elisi

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…A large number of researches have highlighted novel emerging data on HPSE in autophagy and cancer (C. G. Chen & Iozzo, 2022). HPSE enhances tumor growth and chemoresistance, if not all, in part by enhancing autophagy and decreasing rapamycin‐1 (mTOR1) activity (Fu et al, 2020; Shteingauz et al, 2015). However, since the levels of LC3‐II, a protein that specifically binds to autophagosomes, were found to be reduced in cells and tissues of HPSE knockout mice.…”

Section: The Protumorigenic Role Of Hpse In Cancer Progressionmentioning

confidence: 99%

Potential roles of heparanase in cancer therapy: Current trends and future direction

Yang

Yuan

Zhou

et al. 2023

Journal Cellular Physiology

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Heparanase (HPSE; heparanase‐1) is an endo‐β‐glucuronidase capable of degrading the carbohydrate moiety of heparan sulfate proteoglycans, thus modulating and facilitating the remodeling of the extracellular matrix and basement membrane. HPSE activity is strongly associated with major human pathological complications, including but not limited to tumor progress and angiogenesis. Several lines of literature have shown that overexpression of HPSE leads to enhanced tumor growth and metastatic transmission, as well as poor prognosis. Gene silencing of HPSE or treatment of tumor with compounds that block HPSE activity are shown to remarkably attenuate tumor progression. Therefore, targeting HPSE is considered as a potential therapeutical strategy for the treatment of cancer. Intriguingly, recent findings disclose that heparanase‐2 (HPSE‐2), a close homolog of HPSE but lacking enzymatic activity, can also regulate antitumor mechanisms. Given the pleiotropic roles of HPSE, further investigation is in demand to determine the precise mechanism of regulating action of HPSE in different cancer settings. In this review, we first summarize the current understanding of HPSE, such as its structure, subcellular localization, and tissue distribution. Furthermore, we systematically review the pro‐ and antitumorigenic roles and mechanisms of HPSE in cancer progress. In addition, we delineate HPSE inhibitors that have entered clinical trials and their therapeutic potential.

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Heparan sulfate fine‐tunes stromal‐epithelial communication in the prostate gland

Barbosa

Biancardi

Carvalho

2020

Developmental Dynamics

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Several studies reported the concerted and mutual communication between the prostate epithelium and stroma, which determines the final organ architecture and function, but gets awry in cancer. Deciphering the mechanisms involved in this communication is crucial to find new therapeutic strategies. HS sequesters a number of secreted growth factors and cytokines, controlling their bioavailability to the target cells, suggesting that HS is an important regulator of the extracellular matrix (ECM) and a key player in the cell-cell and cell-microenvironment communication during prostate morphogenesis and physiology. We propose that by controlling HS biosynthesis and sulfation pattern, as well as the cleavage of the HS chain and/or the shedding of proteoglycans, epithelial and stromal cells are able to precisely tune the availability of signaling molecules and modulate ligand-receptor interaction and intracellular signal transduction.

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Antitumor activity and structure-activity relationship of heparanase inhibitors: Recent advances

Cited by 5 publications

References 139 publications

New classes of potent heparanase inhibitors from ligand-based virtual screening

New classes of potent heparanase inhibitors from ligand-based virtual screening

Potential roles of heparanase in cancer therapy: Current trends and future direction

Heparan sulfate fine‐tunes stromal‐epithelial communication in the prostate gland

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