Rutgers Molecular Design and Synthesis, Office of Research and Economic Development, Piscataway, New Jersey 08854, United States.
Program of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08901, United States.
J Med Chem. 2021 Feb 25;64(4):2024-2045. doi: 10.1021/acs.jmedchem.0c01360. Epub 2021 Feb 4.
We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure-activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 and .
我们鉴定了一组硫代卡巴腙（TSC）金属离子螯合剂，它们通过一种称为锌金属伴侣（ZMC）的机制来重新激活特定的锌缺乏型 p53 突变体，该机制通过将锌输送到细胞中来恢复锌结合。我们定义了使用这种机制进行结构-活性关系研究所需的生物物理和细胞测定。我们研究了一类与 TSCs 不同的锌支架，它们通过用苯并噻唑基、苯并恶唑基和苯并咪唑基腙取代硫代碳酰基部分。该系列的成员与锌的结合亲和力相似，并且能够像 TSCs 一样重新激活突变型 p53。在啮齿动物中的急性毒性和功效测定表明，其毒性明显低于 TSCs，同时表现出等效的生长抑制作用。我们确定 是一种与铜结合减少的 ZMC，可作为化疗和放疗增敏剂。我们得出结论，苯并噻唑基、苯并恶唑基和苯并咪唑基腙可以作为 ZMC 来重新激活突变型 p53 和 。
