Manaswiyoungkul Pimyupa, de Araujo Elvin D, Gunning Patrick T
Department of Chemistry , University of Toronto , 80 St. George Street , Toronto , Ontario M5S 3H6 , Canada.
Department of Chemical and Physical Sciences , University of Toronto Mississauga , 3359 Mississauga Rd N. , Mississauga , Ontario L5L 1C6 , Canada . Email:
RSC Med Chem. 2019 Dec 23;11(1):51-71. doi: 10.1039/c9md00442d. eCollection 2020 Jan 1.
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.
蛋白质异戊二烯化是包括癌症和获得性免疫缺陷综合征（艾滋病）在内的多种疾病中的关键介质。治疗干预主要集中在直接靶向异戊二烯转移酶，即法尼基转移酶（FTase）和γ-谷氨酰转移酶I和II。迄今为止，几种药物已进入临床试验阶段，虽然前景乐观，但由于脱靶效应和机体激活的补偿机制导致耐药性，它们尚未在医学环境中获得批准。虽然双抑制剂的开发减轻了不良副作用，但效力对于临床开发而言仍不理想。另一种方法是拮抗上游甲羟戊酸途径的酶，即法尼基焦磷酸合酶（FPPS）和牻牛儿基牻牛儿基焦磷酸合酶（GGPPS），它们介导异戊二烯化以及胆固醇合成。这些抑制剂的开发为双重抑制癌症驱动的异戊二烯化以及胆固醇积累带来了新的机遇。在此，我们重点介绍针对异戊二烯化机制的抑制剂开发进展。
