The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.

中文翻译：

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DHODH 抑制剂可增加 p53 合成，并通过阻断 p53 降解来增强肿瘤细胞杀伤力。

自从发现 p53 作为肿瘤抑制因子以来，开发激活肿瘤中野生型 p53 的非基因毒性疗法引起了人们的极大兴趣。在此，我们报告了细胞中 100 多种激活 p53 的小分子的鉴定。我们阐明了手性四氢吲唑（HZ00）的作用机制，并通过靶点解卷积，推断其活性对映体（R）-HZ00可抑制二氢乳清酸脱氢酶（DHODH）。(R)-HZ05/DHODH 复合物的晶体结构揭示了 HZ05（一种更有效的类似物）的手性特异性。p53 激活剂中还详细介绍了其他 12 种 DHODH 抑制剂化学型，这表明 DHODH 是结构多样的化合物的常见靶标。我们观察到 HZ 化合物在 S 期积累癌细胞，增加 p53 合成，并与 p53 降解抑制剂协同作用，减少体内肿瘤生长。因此，我们提出了一种通过 p53 促进癌细胞杀伤的策略，而不是其可逆的细胞周期阻滞作用。