Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines.
Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines.
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DOI：
10.1016/j.ejmech.2018.04.035
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发表时间：
2018-05-25
影响因子：
6.7
通讯作者：
Fersht AR
中科院分区：
文献类型：
--
作者：
Baud MGJ;Bauer MR;Verduci L;Dingler FA;Patel KJ;Horil Roy D;Joerger AC;Fersht AR
许多癌症具有通过突变失活的肿瘤抑制因子p53，使得用小分子重新激活突变型p53成为开发新型抗癌疗法的有希望的策略。致癌的p53突变Y220 C，每年约有100，000例癌症病例，在DNA结合结构域中产生扩展的表面裂缝，使p53不稳定并导致变性和聚集。在这里，我们描述了一类新型小分子Y220 C稳定剂的结构导向设计以及在此过程中开发的具有挑战性的合成路线。合成的化学探针MB 710是一种氨基苯并噻唑衍生物，与Y220 C口袋紧密结合，并在体外稳定p53-Y220 C。MB 710的乙酰胺类似物MB 725在几种p53-Y220 C癌细胞系中诱导选择性活力降低，而在对照细胞系中耐受良好。生存力的降低与p53靶基因（如BTG 2、p21、p53 A、FAS、TNF和TNFRSF 10 B）的增加和选择性转录相关，这些基因促进细胞凋亡和细胞周期阻滞，表明化合物介导的Y220 C突变体的转录激活。我们的数据提供了一个框架，开发一类有效的，无毒的化合物，用于重新激活Y220 C突变体的抗癌治疗。概念验证分子在体外稳定致癌蛋白p53-Y220 C。分子MB 725在p53-Y220 C癌细胞中显示出选择性抗癌活性。抗癌活性与MB 725增强p53信号传导相关。
Many cancers have the tumor suppressor p53 inactivated by mutation, making reactivation of mutant p53 with small molecules a promising strategy for the development of novel anticancer therapeutics. The oncogenic p53 mutation Y220C, which accounts for approximately 100,000 cancer cases per year, creates an extended surface crevice in the DNA-binding domain, which destabilizes p53 and causes denaturation and aggregation. Here, we describe the structure-guided design of a novel class of small-molecule Y220C stabilizers and the challenging synthetic routes developed in the process. The synthesized chemical probe MB710, an aminobenzothiazole derivative, binds tightly to the Y220C pocket and stabilizes p53-Y220C in vitro. MB725, an ethylamide analogue of MB710, induced selective viability reduction in several p53-Y220C cancer cell lines while being well tolerated in control cell lines. Reduction of viability correlated with increased and selective transcription of p53 target genes such as BTG2, p21, PUMA, FAS, TNF, and TNFRSF10B, which promote apoptosis and cell cycle arrest, suggesting compound-mediated transcriptional activation of the Y220C mutant. Our data provide a framework for the development of a class of potent, non-toxic compounds for reactivating the Y220C mutant in anticancer therapy. Proof-of-concept molecules stabilize the oncogenic protein p53-Y220C in vitro. Molecule MB725 shows selective anticancer activity in p53-Y220C cancer cells. Anticancer activity correlates with enhancement of p53 signaling by MB725.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
2.9
作者：
Jacobson, MP;Pincus, DL;Friesner, RA
通讯作者：
Friesner, RA
影响因子：
8
作者：
Bullock, AN;Henckel, J;Fersht, AR
通讯作者：
Fersht, AR
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
5.6
作者：
Capuzzi SJ;Muratov EN;Tropsha A
通讯作者：
Tropsha A