Zinc Metallochaperones Reactivate Mutant p53 Using an ON/OFF Switch Mechanism: A New Paradigm in Cancer Therapeutics.
Zinc Metallochaperones Reactivate Mutant p53 Using an ON/OFF Switch Mechanism: A New Paradigm in Cancer Therapeutics.
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DOI：
10.1158/1078-0432.ccr-18-0822
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发表时间：
2018-09-15
期刊：
影响因子：
--
通讯作者：
Carpizo DR
中科院分区：
文献类型：
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作者：
Yu X;Kogan S;Chen Y;Tsang AT;Withers T;Lin H;Gilleran J;Buckley B;Moore D;Bertino J;Chan C;Kimball SD;Loh SN;Carpizo DR
锌金属伴侣蛋白（ZMCs）是一类新型的抗癌药物，其通过提高和缓冲细胞内锌水平以充分恢复锌结合来重新激活缺锌突变体p53。ZMC的体外药效学表明，p53突变体活性在4 - 6小时开启，在24小时关闭。我们试图了解这种调节的机制，并将这些发现转化为临床前。我们进一步寻求创新ZMC的制剂以提高功效。我们进行了体外机制研究，以确定细胞锌稳态机制在ZMCs的瞬时药效学中的作用。我们使用基因工程鼠胰腺癌模型（KPC）进行临床前药代动力学（PK）、药效学（PD）和功效研究，以转化这些机制发现并研究新型ZMC制剂。在体外，将锌恢复到其生理水平的细胞锌稳态机制在ZMC药效学中起到OFF开关的作用。体内PK研究表明，ZMC具有短的半衰期（<30分钟），这足以显著改善表达锌缺乏等位基因（p53R172H）的小鼠的存活率，而对表达非锌缺乏等位基因（p53R270H）的小鼠没有影响。我们合成了一种新的药物制剂与锌的复合物，并证明这显着提高了ZMC 1的生存率。细胞锌稳态机制在ZMC药效学中起OFF开关的作用，表明短暂的p53突变体再激活足以达到靶向疗效。与锌复合合成的ZMC是一种改进的制剂。
Zinc metallochaperones (ZMCs) are a new class of anti-cancer drugs that reactivate zinc deficient mutant p53 by raising and buffering intracellular zinc levels sufficiently to restore zinc binding. In vitro pharmacodynamics of ZMCs indicate that p53 mutant activity is ON by 4–6 hours and is OFF by 24. We sought to understand the mechanism of this regulation and to translate these findings pre-clinically. We further sought to innovate the formulation of ZMCs to improve efficacy. We performed in vitro mechanistic studies to determine the role of cellular zinc homeostatic mechanisms in the transient pharmacodynamics of ZMCs. We conducted pre-clinical pharmacokinetic (PK), pharmacodymanic (PD) and efficacy studies using a genetically engineered murine pancreatic cancer model (KPC) to translate these mechanistic findings and investigate a novel ZMC formulation. In vitro, cellular zinc homeostatic mechanisms that restore zinc to its physiologic levels function as the OFF switch in ZMC pharmacodynamics. In vivo PK studies indicate that ZMCs have a short half life (<30 minutes), which is sufficient to significantly improve survival in mice expressing a zinc deficient allele (p53R172H) while having no effect in mice expressing a non-zinc deficient allele (p53R270H). We synthesized a novel formulation of the drug in complex with zinc and demonstrate this significantly improves survival over ZMC1. Cellular zinc homeostatic mechanisms function as an OFF switch in ZMC pharmacodynamics indicating that a brief period of p53 mutant reactivation is sufficient for on-target efficacy. ZMCs synthesized in complex with zinc are an improved formulation.