LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal.
Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.
Biochim Biophys Acta Gen Subj. 2020 Jan;1864(1):129440. doi: 10.1016/j.bbagen.2019.129440. Epub 2019 Sep 16.
Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1.
By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced.
SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53.
This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status.
半数人类癌症存在使 p53 失活的 TP53 突变，从而丧失肿瘤抑制作用。因此，通过恢复野生型（wt）样功能使突变（mut）p53 重新激活是癌症治疗中最有前途的治疗策略之一。最近，我们报道了（S）-色氨酸衍生的恶唑并异吲哚啉酮 SLMP53-1 是一种新的 wt 和 mutp53 R280K 重新激活剂，具有体外和体内依赖 p53 的抗肿瘤活性。本工作旨在阐明 SLMP53-1 对 mutp53 的重新激活机制。
通过细胞热转移测定（CETSA），表明 SLMP53-1 诱导 wt 和 mutp53 R280K 热稳定性，这表明与这些蛋白质存在分子间相互作用。因此，对 wt 和 mutp53 R280K DNA 结合域与 SLMP53-1 的计算机模拟研究表明，该化合物结合在 p53 同源二聚体与 DNA 小沟的界面上。此外，使用酵母和过表达不同高度流行的 mutp53 的 p53 缺失肿瘤细胞，证明了 SLMP53-1 重新激活多种 mutp53 的能力。
SLMP53-1 是一种 p53 激活剂，能够直接靶向 wt 和一组热点 mutp53。
这项工作加强了 SLMP53-1 在治疗携带不同 p53 状态的癌症患者中的令人鼓舞的应用。
