Volgograd State Technical University, Volgograd 400005, Russia.
Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (branch) Volgograd State Technical University, Volzhsky 404121, Russia.
J Med Chem. 2021 May 27;64(10):6621-6633. doi: 10.1021/acs.jmedchem.0c01971. Epub 2021 May 7.
Mutant p53 rescue by small molecules is a promising therapeutic strategy. In this structure-activity relationship study, we examined a series of adamantyl isothiocyanates (Ad-ITCs) to discover novel agents as therapeutics by targeting mutant p53. We demonstrated that the alkyl chain connecting adamantane and ITC is a crucial determinant for Ad-ITC inhibitory potency. Ad-ITC with the longest chain between ITC and adamantane displayed the maximum growth inhibition in p53, p53, or p53 mutant cells. Ad-ITC acted in a mutant p53-dependent manner. It rescued p53 and p53 mutants, thereby resulting in upregulating canonical wild-type (WT) p53 targets and phosphorylating ATM. Ad-ISeC with selenium showed a significantly enhanced inhibitory potency, without affecting its ability to rescue mutant p53. Ad-ITCs selectively depleted mutant p53, but not the WT, and this activity correlates with their inhibitory potencies. These data suggest that Ad-ITCs may serve as novel promising leads for the p53-targeted drug development.
小分子拯救突变型 p53 是一种很有前途的治疗策略。在这项构效关系研究中，我们研究了一系列金刚烷异硫氰酸酯（Ad-ITCs），旨在通过靶向突变型 p53 发现新型治疗药物。我们证明，连接金刚烷和 ITC 的烷基链是决定 Ad-ITC 抑制效力的关键因素。在 p53、p53 或 p53 突变细胞中，具有最长碳链的 Ad-ITC 显示出最大的生长抑制作用。Ad-ITC 以依赖突变型 p53 的方式发挥作用。它挽救了 p53 和 p53 突变体，从而上调了典型的野生型（WT）p53 靶标并磷酸化 ATM。含有硒的 Ad-ISeC 显示出显著增强的抑制效力，而不影响其挽救突变型 p53 的能力。Ad-ITCs 选择性地耗尽突变型 p53，而不是 WT，这种活性与其抑制效力相关。这些数据表明，Ad-ITCs 可能成为针对 p53 的药物开发的新型有前途的先导物。
