Doveston Richard G, Kuusk Ave, Andrei Sebastian A, Leysen Seppe, Cao Qing, Castaldi Maria P, Hendricks Adam, Brunsveld Luc, Chen Hongming, Boyd Helen, Ottmann Christian
Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, The Netherlands.
Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
FEBS Lett. 2017 Aug;591(16):2449-2457. doi: 10.1002/1873-3468.12723. Epub 2017 Aug 6.
14-3-3 proteins are positive regulators of the tumor suppressor p53, the mutation of which is implicated in many human cancers. Current strategies for targeting of p53 involve restoration of wild-type function or inhibition of the interaction with MDM2, its key negative regulator. Despite the efficacy of these strategies, the alternate approach of stabilizing the interaction of p53 with positive regulators and, thus, enhancing tumor suppressor activity, has not been explored. Here, we report the first example of small-molecule stabilization of the 14-3-3 - p53 protein-protein interaction (PPI) and demonstrate the potential of this approach as a therapeutic modality. We also observed a disconnect between biophysical and crystallographic data in the presence of a stabilizing molecule, which is unusual in 14-3-3 PPIs.
14-3-3蛋白是肿瘤抑制因子p53的正向调节因子，p53的突变与许多人类癌症相关。目前针对p53的策略包括恢复野生型功能或抑制其与关键负向调节因子MDM2的相互作用。尽管这些策略有效，但稳定p53与正向调节因子的相互作用从而增强肿瘤抑制活性的替代方法尚未得到探索。在此，我们报道了小分子稳定14-3-3-p53蛋白质-蛋白质相互作用（PPI）的首个实例，并证明了这种方法作为一种治疗方式的潜力。我们还观察到在存在稳定分子的情况下生物物理数据与晶体学数据之间存在脱节，这在14-3-3 PPI中并不常见。
