LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
University of Coimbra, Coimbra Chemistry Centre and Department of Chemistry, 3004-535 Coimbra, Portugal.
Cell Rep. 2021 Apr 13;35(2):108982. doi: 10.1016/j.celrep.2021.108982.
Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.
p53 通路的失活是癌症的一个关键事件。因此，重新激活 p53 活性已成为最有吸引力的抗癌治疗策略之一。在这里，我们揭示了一种激活 p53 的抗癌药物（3S）-6,7-双（羟甲基）-5-甲基-3-苯基-1H,3H-吡咯[1,2-c]噻唑（MANIO）。MANIO 对 p53 通路具有显著的选择性，能够激活野生型（WT）p53 并恢复突变型（mut）p53 在人类癌细胞中的 WT 样功能。MANIO 直接与 WT/mutp53 DNA 结合域结合，增强蛋白质的热稳定性、DNA 结合能力和转录活性。MANIO 作为一种针对携带 WT/mutp53 的癌症的高效抗癌剂，在结直肠癌（CRC）的患者来源细胞和异种移植小鼠模型中得到了进一步证明，没有不良副作用的迹象。MANIO 与常规化疗药物协同作用，体外和体内研究预测其具有良好的类药性和药代动力学特性，适合作为临床候选药物。作为单一药物或联合用药，MANIO 将推进抗癌靶向治疗，特别是对携带不同 p53 状态的 CRC 患者有益。
