Discovery of PG545: A Highly Potent and Simultaneous Inhibitor of Angiogenesis, Tumor Growth, and Metastasis

Abstract

Increasing the aglycone lipophilicity of a series of polysulfated oligosaccharide glycoside heparan sulfate (HS) mimetics via attachment of a steroid or long chain alkyl group resulted in compounds with significantly improved in vitro and ex vivo antiangiogenic activity. The compounds potently inhibited heparanase and HS-binding angiogenic growth factors and displayed improved antitumor and antimetastatic activity in vivo compared with the earlier series. Preliminary pharmacokinetic analyses also revealed significant increases in half-life following iv dosing, ultimately supporting less frequent dosing regimens in preclinical tumor models compared with other HS mimetics. The compounds also displayed only mild anticoagulant activity, a common side effect usually associated with HS mimetics. These efforts led to the identification of 3β-cholestanyl 2,3,4,6-tetra-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β-d-glucopyranoside, tridecasodium salt (PG545, 18) as a clinical candidate. Compound 18 was recently evaluated in a phase I clinical trial in cancer patients.

Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation

“…It has been previously demonstrated that the antitumor activity of HS mimetics is primarily mediated through the inhibition of growth factor binding and heparanase activity, which primarily effect tumor angiogenesis and metastasis (13,14,16,22,23,40,41). However, the potential effects of PG545 as an immunomodulatory agent have not been examined.…”

“…Given the important role of heparanase and HS in cancer progression, HS mimetics that inhibit heparanase and compete for the HS-binding domain of angiogenic growth factors have been developed as novel antitumor agents (12,13). Indeed, HS mimetics have demonstrated antitumor activities in multiple preclinical studies of metastatic solid tumors in mice (14)(15)(16)(17).…”

“…In contrast to these agents, PG545 is a single molecular entity, a synthetically manufactured tetrasaccharide with a lipophilic modification. This design not only enhanced antitumor and antimetastatic activity, but also significantly increased in vivo half-life compared with typical HS mimetics (13,14,16,18). In addition, PG545 exhibits very mild anticoagulant activity, a common side effect of HS mimetics (19)(20)(21).…”

“…Although the conventional antitumor mechanism for HS mimetics is the inhibition of angiogenesis and metastasis (13,14,16,22,23), HS and heparanase have been associated with inflammatory responses (12,24,25) and the effects of PG545 on immune cells have not been specifically investigated. In this study, we found that PG545 had potent antitumor activity in murine models of B cell and T cell lymphomas.…”

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

“…Although PG545 appears as a potent inhibitor that attenuates the progression of several carcinomas (19) and lymphomas ( Fig. 1), it also exhibits heparanase-unrelated properties and impedes the signaling of HS-bound growth-and angiogenesispromoting factors (21). To evaluate the role of heparanase in lymphoma growth in a more specific manner, we used a polyclonal Ab (Ab 1453) that neutralizes heparanase enzymatic activity ( Fig.…”