Review articleAntitumor activity and structure-activity relationship of heparanase inhibitors: Recent advances
Graphical abstract
Heparanase (HPSE) inhibitors are classified into three types to be discussed according to interaction with the binding sites of HPSE and participation of growth factors. The antitumor activity and structure-activity relationship are also emphasized.
Introduction
Heparanase (HPSE), an endo-β-D glucuronidase, is exclusively expressed in mammalian cells. It has two isozymes HPSE1 and HPSE2, encoded by two genes respectively, but HPSE2 lacks enzymatic activity and acts predominantly as a negative regulator of HPSE1 [1]. HPSE, usually referred to HPSE1, comprises two functional domains, an (α/β)8 barrel catalytic domain and a β-sandwich C-terminal domain. In the catalytic domain, the residues Glu343 and Glu225 are responsible for the catalytic nucleophile and catalytic acid/base of HPSE enzymatic cleaving activity, respectively [2]. The C-terminal domain has been demonstrated to regulate protein secretion and non-enzymatic activity of HPSE [3]. Significant aggressiveness and chemo-resistance of multiple tumor cells are largely dependent on the enzymatic or non-enzymatic activities of HPSE. On the one hand, HPSE specifically cleaves the β (1,4)-glycosidic bond between residues glucuronic acid and glucosamine (Fig. 1) of heparan sulfate (HS) attached to proteoglycans via enzymatic activity [4], latent pools of growth factors sequestered by HS are subsequently released, posing remodeling of ECM and BM [5]. On the other hand, HPSE regulates gene expression, activates the innate immune system, promotes the formation and release of exosomes and autophagosomes, as well as stimulates signal transduction pathways by virtue of non-enzymatic activity [4]. These HPSE-mediated bio-functions play a strong positive role in regulating tumor-host crosstalk and priming the tumor microenvironment to support tumor growth, metastasis and chemo-resistance.
The inactive pro-HPSE (65 kDa) is a HPSE precursor, which is synthesized in the endoplasmic reticulum (ER), an activity that stimulates signaling cascades to enhance phosphorylation of specific proteins including Akt, Src, and ERK. Then the pro-HPSE is processed in the Golgi and resultant HPSE is stored in the lysosomes and endosomes. Activated HPSE could be released to the extracellular space, the surface of exosomes, and autophagosomes, or even shuttled into the nucleus. HPSE located in late endosomes and lysosomes performs an essential housekeeping role in catabolic processing of internalized heparan sulfate proteoglycans (HPSGs). Extracellular HPSE effects degradation and turnover of cell surface HSPGs via an enzymatic approach. Also, HPSE enters the intracellular to stimulate release of growth factors, which are secreted into the extracellular space, further posing pathological conditions (Fig. 2). Moreover, HPSE in the lysosomes and autophagosomes can positively stimulate the autophagic process through a non-enzymatic mechanism due to downregulation of mTOR1 activity [6,7]. Collectively, the enzymatic and non-enzymatic activities make HPSE a multifunctional molecule that deteriorates aggressiveness and chemo-resistance in multiple tumor cells [[8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]].
As discussed above, HPSE is a promising and potential antitumor target. HPSE inhibition has attracted intense interest as an anticancer strategy. The putative binding site of HPSE orientates as a canyon-like cleft, which is made up of several polar and nonpolar amino acid residues [27]. The resolved co-crystal structure of complex HPSE protein and its substrate provides a powerful design basis for HPSE inhibitors [28]. A trisaccharide is a minimal substrate for HPSE because less than three sugar residues do not well accommodate into the binding cleft of HPSE, and an appropriated sulfation is required for the interaction with HPSE and HS. HPSE inhibitors reported are demonstrated to inhibit HPSE activity through competitively binding to the HS-binding sites of HPSE, or simultaneously binding to the HS-binding sites of HPSE and growth factors, or binding to the non HS-binding sites of HPSE [29]. To date, a series of HPSE inhibitors such as PG545, SST0001, M402 and PI-88 are evaluated in clinical trials for cancer therapy. PG545 exhibited a long plasma half-life and showed an excellent activity against HPSE, and Phase I clinical trials were completed in 2015 [30]. SST0001 exhibited a low-anticoagulant activity, selectively inhibited HPSE and related growth factors [31], and Phase I trials were finished in 2016 [30]. M402 showed a low-anticoagulant activity and a good potential for HPSE inhibition, but it was halted after Phase I trials [30,32]. PI-88 has entered into phase III clinical trials for treating liver cancer [33]. Apparently, HPSE inhibitors are potent and promising anti-cancer agents.
The roles of HPSE in cancer progression are very crucial and widely accepted. Understanding the subtle binding mode of HPSE and its substrates is an attractive solution to cancer therapy. HPSE inhibitors development has demonstrated a promising strategy for suppressing tumor growth, metastasis and chemo-resistance. Although several reviews focusing on the status of natural, chemically modified, and synthetic HPSE inhibitors able to treat various types of malignancies have been reported [30,[34], [35], [36]], the structure-activity relationships are not clearly pointed out. Herein, the recent advance of HPSE inhibitors as promising anti-tumor drugs is stated from a new perspective of interaction with the binding sites of HPSE and participation of growth factors, and the inhibitory activity and structure-activity relationship are highlighted, in hope to provide a novel guiding direction for developing more effective HPSE inhibitors.
Section snippets
Endogenous HP/HS-based HPSE inhibitors
Heparin (HP) is a highly sulfated HS that is an endogenous substrate of HPSE. HS mimics represent good candidates as anticancer agents targeting HPSE inhibition. Heparin mimics act as substrate analogues to competitively inhibit HP binding to HPSE, such as modified heparins and PI-88. These compounds demonstrated the improved activity against HPSE, the excellent bioavailability and the reduced side effects [37]. When co-administered with other anti-cancer agents, tumor resistance was eliminated.
Conclusion and future outlook
Most HPSE inhibitors competitively target to the HS/HP-binding sites of HPSE and thus prevent HS access to the catalytic domains. Structurally, they are divided into two types including carbohydrate-based inhibitors and non-carbohydrate-based ones [29]. For the carbohydrate-based inhibitors, most mainly inhibit HPSE activities as competitive inhibitors of HS, e.g. HS analogues, PI-88, SST0001, M402, PS3, JG3, COs, azasugar-derived analogues, HS-derived glycomimetic clusters, etc. However, PG545
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The work is supported in part by financial support from National Natural Science Foundation of China (No.21772028), General scientific research project of Guangzhou (201804010325) and “Climbing” progress of Guangdong province (pdjh2019a0111, pdjh2020b0139).
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