Targeting prenylation inhibition through the mevalonate pathway,RSC Medicinal Chemistry

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Targeting prenylation inhibition through the mevalonate pathway
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2019/12/23 , DOI: 10.1039/c9md00442d
Pimyupa Manaswiyoungkul ₁ , Elvin D de Araujo ₂ , Patrick T Gunning _{1,

2}

Affiliation

Protein prenylation is a critical mediator in several diseases including cancer and acquired immunodeficiency syndrome (AIDS). Therapeutic intervention has focused primarily on directly targeting the prenyltransferase enzymes, FTase and GGTase I and II. To date, several drugs have advanced to clinical trials and while promising, they have yet to gain approval in a medical setting due to off-target effects and compensatory mechanisms activated by the body which results in drug resistance. While the development of dual inhibitors has mitigated undesirable side effects, potency remains sub-optimal for clinical development. An alternative approach involves antagonizing the upstream mevalonate pathway enzymes, FPPS and GGPPS, which mediate prenylation as well as cholesterol synthesis. The development of these inhibitors presents novel opportunities for dual inhibition of cancer-driven prenylation as well as cholesterol accumulation. Herein, we highlight progress towards the development of inhibitors against the prenylation machinery.

中文翻译：

通过甲羟戊酸途径靶向异戊二烯化抑制

蛋白质异戊二烯化是包括癌症和获得性免疫缺陷综合症（艾滋病）在内的多种疾病的关键介质。治疗干预主要集中于直接针对异戊二烯基转移酶、FTase 和 GGTase I 和 II。迄今为止，几种药物已进入临床试验，虽然前景广阔，但由于脱靶效应和身体激活的补偿机制导致耐药性，它们尚未获得医疗环境的批准。虽然双重抑制剂的开发减轻了不良副作用，但其效力对于临床开发而言仍然次优。另一种方法涉及拮抗上游甲羟戊酸途径酶 FPPS 和 GGPPS，它们介导异戊二烯化和胆固醇合成。这些抑制剂的开发为双重抑制癌症驱动的异戊二烯化和胆固醇积累提供了新的机会。在此，我们重点介绍异戊二烯化机制抑制剂的开发进展。

更新日期：2020-02-13

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