Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C.
Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C.
复制标题
DOI：
10.1021/acsptsci.2c00164
复制
发表时间：
2022-11-11
影响因子：
--
通讯作者：
Baud, Matthias G J
中科院分区：
文献类型：
--
作者：
Stephenson Clarke, Joseph R;Douglas, Leon R;Duriez, Patrick J;Balourdas, Dimitrios-Ilias;Joerger, Andreas C;Khadiullina, Raniya;Bulatov, Emil;Baud, Matthias G J
肿瘤抑制蛋白p53在大多数人类癌症中是失活的，并且仍然是开发新药以重新激活其肿瘤抑制活性用于抗癌疗法的主要靶点。致癌p53突变体Y220 C每年约有125，000例新发癌症病例，是总体上最普遍的p53突变体之一。它在DNA结合结构域的表面具有一个狭窄的突变诱导口袋，使p53不稳定，导致其快速变性和聚集。在这里，我们提出了结构指导的发展，高亲和力的小分子稳定p53-Y220 C在体外，沿着的合成路线的过程中，在体外结构-活性关系的数据，并确认其结合模式的蛋白质X射线晶体学。我们公开了两种在体外显示亚微摩尔结合亲和力的新化学探针，这是自2008年发现Y220 C的第一个小分子配体以来的一个重要里程碑。新的化学探针JC 744显示Kd = 320 nM，沿着具有有效的体外蛋白稳定性。因此，这项研究代表了高亲和力Y220 C配体用于临床评价的重大进展。
The tumor suppressor protein p53 is inactivated in the majority of human cancers and remains a prime target for developing new drugs to reactivate its tumor suppressing activity for anticancer therapies. The oncogenic p53 mutant Y220C accounts for approximately 125,000 new cancer cases per annum and is one of the most prevalent p53 mutants overall. It harbors a narrow, mutationally induced pocket at the surface of the DNA-binding domain that destabilizes p53, leading to its rapid denaturation and aggregation. Here, we present the structure-guided development of high-affinity small molecules stabilizing p53-Y220C in vitro, along with the synthetic routes developed in the process, in vitro structure–activity relationship data, and confirmation of their binding mode by protein X-ray crystallography. We disclose two new chemical probes displaying sub-micromolar binding affinity in vitro, marking an important milestone since the discovery of the first small-molecule ligand of Y220C in 2008. New chemical probe JC744 displayed a Kd = 320 nM, along with potent in vitro protein stabilization. This study, therefore, represents a significant advance toward high-affinity Y220C ligands for clinical evaluation.