College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
King Abdullah International Medical Research Center, King Saud Bin Abdelaziz University for Health Sciences, Jeddah 21423, Saudi Arabia.
Int J Mol Sci. 2024 Oct 20;25(20):11293. doi: 10.3390/ijms252011293.
Geldanamycin, an -macrolide composed of a rigid benzoquinone ring and an aliphatic -bridge, was isolated from . Geldanamycin is a potent heat shock protein inhibitor with remarkable antiproliferative activity. However, it shows pronounced hepatotoxicity in animal models and unfavorable pharmacokinetic properties. Four geldanamycin analogs have progressed through various phases of clinical trials, but none have yet completed clinical evaluation or received FDA approval. To enhance the efficacy of these Hsp90 inhibitors, strategies such as prodrug approaches or nanocarrier delivery systems could be employed to minimize systemic and organ toxicity. Furthermore, exploring new drug combinations may help overcome resistance, potentially improving therapeutic outcomes. This review discusses the mechanism of action of geldanamycin, its pharmacokinetic properties, and the various approaches employed to alleviate its toxicity and maximize its clinical efficacy. The main focus is on those derivatives that have progressed to clinical trials or that have shown important in vivo activity in preclinical models.
格尔德霉素是一种由刚性苯醌环和脂肪桥组成的大环内酯类化合物，从 Streptomyces hygroscopicus 中分离得到。格尔德霉素是一种有效的热休克蛋白抑制剂，具有显著的抗增殖活性。然而，它在动物模型中表现出明显的肝毒性和不良的药代动力学特性。有 4 种格尔德霉素类似物已经进入了不同阶段的临床试验，但没有一种完成了临床评估或获得了 FDA 的批准。为了提高这些 HSP90 抑制剂的疗效，可以采用前药方法或纳米载体递送系统等策略，以最小化全身和器官毒性。此外，探索新的药物组合可能有助于克服耐药性，从而提高治疗效果。本文综述了格尔德霉素的作用机制、药代动力学特性以及减轻其毒性和提高临床疗效的各种方法。重点介绍了那些已经进入临床试验或在临床前模型中表现出重要体内活性的衍生物。
