PI-88 及相关硫酸乙酰肝素类似物。
PI-88 and Related Heparan Sulfate Mimetics.
机构信息
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia.
出版信息
Adv Exp Med Biol. 2020;1221:473-491. doi: 10.1007/978-3-030-34521-1_19.
The heparan sulfate mimetic PI-88 (muparfostat) is a complex mixture of sulfated oligosaccharides that was identified in the late 1990s as a potent inhibitor of heparanase. In preclinical animal models it was shown to block angiogenesis, metastasis and tumor growth, and subsequently became the first heparanase inhibitor to enter clinical trials for cancer. It progressed to Phase III trials but ultimately was not approved for use. Herein we summarize the preparation, physicochemical and biological properties of PI-88, and discuss preclinical/clinical and structure-activity relationship studies. In addition, we discuss the PI-88-inspired development of related HS mimetic heparanase inhibitors with improved properties, ultimately leading to the discovery of PG545 (pixatimod) which is currently in clinical trials.
硫酸乙酰肝素类似物 PI-88（米卡芬净）是一种复杂的硫酸化寡糖混合物，于 20 世纪 90 年代后期被鉴定为一种强效的肝素酶抑制剂。在临床前动物模型中，它被证明可以阻止血管生成、转移和肿瘤生长，随后成为第一个进入癌症临床试验的肝素酶抑制剂。它进入了 III 期临床试验，但最终未被批准使用。本文总结了 PI-88 的制备、理化性质和生物学特性，并讨论了临床前/临床和构效关系研究。此外，我们还讨论了受 PI-88 启发的具有改善性能的相关 HS 类似物肝素酶抑制剂的开发，最终导致了 PG545（培西他滨）的发现，目前正在临床试验中。
Zotero 插件