*5.3. Heparan Sulfate Mimetics Development and Clinical Trials* 5.3.1. Heparan Sulfate Mimetics Rational

Heparin derivatives and HS mimetics are drawing great attention for developing new therapeutics for diverse diseases, from inflammation to neurodegenerative disorders and cancer [207]. HS mimetics overcome a problem known for more than half a century in Medicine related to heparin use. Heparin is an anticoagulant drug which has been widely used and remains one of the main drugs for prophylaxis and treatment of thrombosis [236]. Thrombosis is a common complication of cancer patients. The use of heparin has improved the survival rate of cancer patients [237]. The functional roles of heparin seem far more than anticoagulation, since a number of additional beneficial effects have been observed for heparin in other diseases than thrombosis [238]. However, heparin is an animalderived heterogeneous polysaccharide, therefore the potential risk of contamination and its complicated molecular structure restrict its use. Therefore, and taking in consideration the high structural similarities between heparin and HS, it was tested whether heparin interferes with HS interactions with its ligands mainly through the hamper of angiogenic growth factors, like VEGF and FGF, selectins, and HPSE [239,240]. Indeed, in vitro analyses have shown that heparin is able to inhibit HPSE activity [240]. Since it is important to restrict heparin anticoagulant activity, due to haemorrhagic issues, efforts were made to eliminate the anticoagulation activity by chemical modification.

Roneparstat (SST0001) was the first synthetic product based on this premise. SST0001 is a 100% *N*-acetylated and glycol split heparin synthetic molecule [241]. The SST0001 HPSE inhibitory effect was confirmed on myeloma cell growth, and therefore, it is being evaluated for the treatment of multiple myeloma [242].

The principle of using HS mimetics is to interfere with the interactions between HS and its molecular partners (Figure 2C). There are two types of HS mimetics: (1) Synthetic saccharide-based HS assembled from a backbone sugar structure; and (2) non-sugar scaffold negatively charged with sulfates, sulfonates, carboxylates and/or phosphates [205]. SST0001 and other HS-mimicking compounds main attribution is to inhibit HPSE and compete for HS binding with several growth factors, having impact on cancer by preventing angiogenic and metastatic events [218,243]. In summary, HS mimetics have been shown to enhance antitumour effects, particularly when combined with standard therapies.
