Ayral-Kaloustian S, Zhang N, Beyer C
Chemical Sciences, Discovery Medicinal Chemistry, Wyeth Research, Pearl River, NY 10965, USA.
Methods Find Exp Clin Pharmacol. 2009 Sep;31(7):443-7. doi: 10.1358/mf.2009.31.7.1410793.
Antimitotic agents are among the most effective drugs for the treatment of solid tumors and metastatic cancer. These drugs promote cell death by interfering with the crucial structural and regulatory function of microtubules in cells. Most of the agents of clinical relevance are natural products or semisynthetic derivatives thereof, and they fall into two major classes: microtubule stabilizers such as the taxanes, which enhance tubulin polymerization, and microtubule destabilizers such as the Vinca alkaloids, which lead to the depolymerization of existing microtubules. While these drugs are effective in inhibiting the progression of certain types of tumors, their utility is limited in part by incomplete tumor responses and/or significant side effects. In addition, inherent resistance is encountered in many tumor types, or acquired resistance may occur as a result of multiple cycles of therapy. Cevipabulin (TTI-237) is a novel, small synthetic molecule with an unusual biological mode of action. It appears to bind at the vinca site, but exhibits some properties similar to those of taxane-site ligands, such as enhancing tubulin polymerization. The compound works against a variety of tumors, including those resistant to paclitaxel and vincristine. Furthermore, cevipabulin is stable and water-soluble, and can be administered i.v. or p.o. in saline. It can be synthesized in bulk quantities efficiently. Based on these properties, cevipabulin was selected for clinical development.
抗有丝分裂药物是治疗实体瘤和转移性癌症最有效的药物之一。这些药物通过干扰细胞中微管的关键结构和调节功能来促进细胞死亡。大多数具有临床相关性的药物是天然产物或其半合成衍生物，它们分为两大类：微管稳定剂，如紫杉烷类，可增强微管蛋白聚合；微管破坏剂，如长春花生物碱，可导致现有微管解聚。虽然这些药物在抑制某些类型肿瘤的进展方面有效，但其效用部分受到不完全的肿瘤反应和/或显著副作用的限制。此外，在许多肿瘤类型中会出现固有耐药性，或者由于多个治疗周期可能会产生获得性耐药性。西维帕布林（TTI-237）是一种新型的小合成分子，具有不同寻常的生物学作用模式。它似乎结合在长春花碱位点，但表现出一些与紫杉烷类位点配体相似的特性，如增强微管蛋白聚合。该化合物对多种肿瘤有效，包括对紫杉醇和长春新碱耐药的肿瘤。此外，西维帕布林稳定且水溶性好，可通过静脉注射或口服给药于盐溶液中。它可以高效地大量合成。基于这些特性，西维帕布林被选用于临床开发。
