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Target id: 2996

Nomenclature: heparanase

Family: 3.2.1.- Glycosidases

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 543 4q21.23 HPSE heparanase
Mouse - 535 5 E4 Hpse heparanase
Rat - 536 14p22 Hpse heparanase
Previous and Unofficial Names Click here for help
Database Links Click here for help
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
RefSeq Nucleotide
RefSeq Protein
Enzyme Reaction Click here for help
EC Number:
Description Reaction Reference
Cleavage of heparan sulfate glycosaminoglycans from proteoglycan core proteins and degradation of these to small oligosaccharides. Endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan

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Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
pixatimod Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.2 pKi 8
pKi 8.2 (Ki 6.1x10-9 M) [8]
Inhibitor Comments
Muparfostat (PI-88) is a mixture of highly sulfated mannose-containing di- to hexa-saccharides that is a heparan sulfate mimetic heparanase inhibitor. This mixture inhibits heparanase with a Ki of 7.9 nM [8-9].
Immunopharmacology Comments
Heparanase has been studied as a novel drug target associated with the immune response and inflammation [2-3], as well as immune surveillance within tumours [12]. The clinical potential of heparin mimetics that acts as heparanase inhibitors is reviewed by Mohamed and Coombe (2017) [11]. Heparan sulphate mimetics are being investigated as angoigenesis inhibitors for cancer immuno-therapy. Heparanase derived from NK cells appears to be critical for NK cell infiltration into tumours, and thereby plays a regulatory role in tumour progression and metastasis [12]. This information suggests that heparanase inhibitors may compromise NK cells' immune surveillance in the tumour microenvironment and could in fact promote tumour progression and metastasis, an undesireable side-effect with the potential to limit the anti-tumour efficacy of heparanase inhibitors.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
General Comments
Heparanase is an endoglycosidase that cleaves heparan sulfate proteoglycans into heparan sulfate side chains and core proteoglycans. It is active as a heterodimer of 8 and 50 kDa protein chains that are post-translationally cleaved from the prepropeptide. Heparanase catalysis requires acidic pH, such as that produced in the tumour microenvironment and at inflammatory sites. Heparan sulfate is an essential component of the extracellular matrix (ECM) that inhibits tumour invasion and metastasis. Heparanase promotes tumour growth by cleaving heparan sulfate proteoglycans in the ECM and releasing heparan sulfate-bound angiogenic growth factors. Heparanase-driven ECM degradation augments tumour invasion and metastasis.

Heparanase has been studied as a novel drug target because of its role in angiogenesis and tumour metastasis [4,12-13], and associations with viral pathogenesis [1,14] and inflammation [2-3,12]. Heparan sulphate mimetics are being investigated as angiogenesis and metastasis inhibitors for cancer therapy [6-7]. Muparfostat (PI-88) [9] is a mixture of highly sulfated mannose-containing di- to hexa-saccharides that reached Phase 3 development as adjuvant therapy in patients with hepatocellular carcinoma. Phase 2 trial results had indicated potential clinical efficacy [10], but the programme was terminated due to concerns identified by interim anaylsis of the Phase 3 studies, and for business reasons. Pixatimod (PG545) is a heparan sulphate mimetic that contains a single molecular entity, and which is in early clinical development for the treatment of advanced solid tumours [5].


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1. Agelidis AM, Hadigal SR, Jaishankar D, Shukla D. (2017) Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1. Cell Rep, 20 (2): 439-450. [PMID:28700944]

2. Changyaleket B, Chong ZZ, Dull RO, Nanegrungsunk D, Xu H. (2017) Heparanase promotes neuroinflammatory response during subarachnoid hemorrhage in rats. J Neuroinflammation, 14 (1): 137. [PMID:28720149]

3. Changyaleket B, Deliu Z, Chignalia AZ, Feinstein DL. (2017) Heparanase: Potential roles in multiple sclerosis. J Neuroimmunol, 310: 72-81. [PMID:28778449]

4. Chen X, Jiang W, Yue C, Zhang W, Tong C, Dai D, Cheng B, Huang C, Lu L. (2017) Heparanase Contributes To Trans-Endothelial Migration of Hepatocellular Carcinoma Cells. J Cancer, 8 (16): 3309-3317. [PMID:29158804]

5. Dredge K, Brennan TV, Hammond E, Lickliter JD, Lin L, Bampton D, Handley P, Lankesheer F, Morrish G, Yang Y et al.. (2018) A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours. Br J Cancer, 118 (8): 1035-1041. [PMID:29531325]

6. Dredge K, Hammond E, Davis K, Li CP, Liu L, Johnstone K, Handley P, Wimmer N, Gonda TJ, Gautam A et al.. (2010) The PG500 series: novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy. Invest New Drugs, 28 (3): 276-83. [PMID:19357810]

7. Dredge K, Hammond E, Handley P, Gonda TJ, Smith MT, Vincent C, Brandt R, Ferro V, Bytheway I. (2011) PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models. Br J Cancer, 104 (4): 635-42. [PMID:21285983]

8. Ferro V, Liu L, Johnstone KD, Wimmer N, Karoli T, Handley P, Rowley J, Dredge K, Li CP, Hammond E et al.. (2012) Discovery of PG545: a highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis. J Med Chem, 55 (8): 3804-13. [PMID:22458531]

9. Johnstone KD, Karoli T, Liu L, Dredge K, Copeman E, Li CP, Davis K, Hammond E, Bytheway I, Kostewicz E et al.. (2010) Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth. J Med Chem, 53 (4): 1686-99. [PMID:20128596]

10. Liu CJ, Chang J, Lee PH, Lin DY, Wu CC, Jeng LB, Lin YJ, Mok KT, Lee WC, Yeh HZ et al.. (2014) Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence. World J Gastroenterol, 20 (32): 11384-93. [PMID:25170226]

11. Mohamed S, Coombe DR. (2017) Heparin Mimetics: Their Therapeutic Potential. Pharmaceuticals (Basel), 10 (4). [PMID:28974047]

12. Putz EM, Mayfosh AJ, Kos K, Barkauskas DS, Nakamura K, Town L, Goodall KJ, Yee DY, Poon IK, Baschuk N et al.. (2017) NK cell heparanase controls tumor invasion and immune surveillance. J Clin Invest, 127 (7): 2777-2788. [PMID:28581441]

13. Ricciuti B, Foglietta J, Chiari R, Sahebkar A, Banach M, Bianconi V, Pirro M. (2017) Emerging enzymatic targets controlling angiogenesis in cancer: preclinical evidence and potential clinical applications. Med Oncol, 35 (1): 4. [PMID:29209837]

14. Thakkar N, Yadavalli T, Jaishankar D, Shukla D. (2017) Emerging Roles of Heparanase in Viral Pathogenesis. Pathogens, 6 (3). [PMID:28927006]

How to cite this page

3.2.1.- Glycosidases: heparanase. Last modified on 30/03/2018. Accessed on 16/06/2024. IUPHAR/BPS Guide to PHARMACOLOGY,