Abstract
Human heparanase (HPSE) is an endo‐b‐D‐glucuronidase that cleaves glycosaminoglycan (GAG) chains of heparan sulfate proteoglycans (HSPGs) present on cell surfaces and in the extracellular matrix (ECM). HPSE is upregulated in many types of cancers and promotes an aggressive tumor growth leading to metastasis. HPSE is also involved in various other pathologies such as inflammation, thrombosis, atherosclerosis and kidney dysfunction. Because of these important roles, HPSE is a promising target for the development of a novel therapeutic. In fact, several HS mimetics including PI‐88, SST000, PG545, and M402 are being pursued in clinical trials. Yet, each of these is saccharide mimetics of HS, which are either polymeric, and therefore heterogeneous, or are very difficult to prepare. We have pursued the idea that small, synthetic agents called Non‐Saccharide Glycosaminoglycan Mimetics (NSGMs) would modulate pathological responses such cancer, coagulation, and inflammation in which GAGs play important roles. We hypothesized that an optimal small, synthetic NSGM that potently binds to HPSE would inhibit its enzymatic activity and lead to a novel, anti‐angiogenesis agent. Therefore, we screened an in‐house library 70 NSGMs and identified 35 agents that displayed reasonable HPSE inhibition. Detailed studies using a one‐step FRET assay as well as UPLC‐MS/MS assay showed that an NSGM labeled as G2.2 exhibited high anti‐HPSE potency of 3.2±0.3 μM. G2.2 is synthesized in five simple steps in high overall yields (>30%) from readily available natural product quercetin. G2.2 significantly blocked the migration and invasion of HT‐29 spheroid cells compared to vehicle‐treated control cells. The highly promising anti‐HPSE agent is currently being investigated in animal models of angiogenesis.Support or Funding InformationP‐01 HL107152This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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