Study on Medicinal Chemistry, Chemical Biology and Chemical Pharmaceutics of Anticancer Drug Based on the Microtubule Targeting Agents

我们致力于开发新型微管解聚剂，其重点是天然二酮哌嗪，苯拉组氨酸，已成功地在II期临床试验中创建了一种高效抗癌候选药物“普那布林”，作为“血管破坏剂”，其诱导肿瘤选择性血管塌陷。已进行普那布林的SAR研究，以开发更有效的衍生物。二苯甲酮衍生物KPU-133表现出比普那布林高30倍的细胞毒性，将是进一步药物开发的有希望的候选物。此外，为了改善普那布林的低水溶性（<0.1 mg/mL），开发了一种高度水溶性的前药（6 mg/mL水溶液），通过从monolactin到DKP的独特骨架转化来再生母体药物。另一方面，使用化学探针对微管蛋白结合位点的研究表明，普那布林衍生物可以在α-和β-微管蛋白的界面区域相互作用，该界面区域与秋水仙素结合位点部分重叠。

Our efforts to develop novel m icrotubule depolymerization agents, which was focused on a natural diketopiperazine, phenylahistin, have succeeded in creating a highly potent anticancer drug candidate "Plinabulin" in Phase II clinical trials as a "vascular disrupting agent", which induces tumor-selective vascular collapse. SAR study from plinabulin has been conducted to develop more potent derivatives. A benzophenone derivative KPU-133 exhibited a 30-times higher cytotoxicity than plinabulin and would be promising candidates for further drug development. Moreover, to improve the low water-solubility of plinabulin(<0.1 mg/mL), a highly water-soluble prodrug(6 mg/mL in water) was developed to regenerate the parent drug by a unique skeletal transformation from monolactim to DKP. On the other hand, investigation of the tubulin-binding site using chemical probes indicated that plinabulin derivatives could interact in the interfacial region of α-and β-tubulin, which partially overlaps with the colchicine-binding site.