A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.
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DOI：
10.1038/s41467-018-03441-3
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发表时间：
2018-03-16
影响因子：
16.6
通讯作者：
Laín S
中科院分区：
文献类型：
--
作者：
Ladds MJGW;van Leeuwen IMM;Drummond CJ;Chu S;Healy AR;Popova G;Pastor Fernández A;Mollick T;Darekar S;Sedimbi SK;Nekulova M;Sachweh MCC;Campbell J;Higgins M;Tuck C;Popa M;Safont MM;Gelebart P;Fandalyuk Z;Thompson AM;Svensson R;Gustavsson AL;Johansson L;Färnegårdh K;Yngve U;Saleh A;Haraldsson M;D'Hollander ACA;Franco M;Zhao Y;Håkansson M;Walse B;Larsson K;Peat EM;Pelechano V;Lunec J;Vojtesek B;Carmena M;Earnshaw WC;McCarthy AR;Westwood NJ;Arsenian-Henriksson M;Lane DP;Bhatia R;McCormack E;Laín S
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的非遗传毒性疗法引起了极大的兴趣。在这里，我们报告了100多个小分子激活细胞中的p53。我们阐明了手性四氢吲唑（HZ 00）的作用机制，并通过靶向去卷积，我们推断其活性对映体（R）-HZ 00，抑制二氢乳清酸脱氢酶（DHODH）。（R）-HZ 05/DHODH复合物的晶体结构揭示了HZ 05（一种更有效的类似物）的手性特异性。在p53激活剂中详细描述了12种其他DHODH抑制剂化学型，这将DHODH鉴定为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以减少体内肿瘤生长。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。肿瘤抑制因子p53的激活是癌症治疗中有前途的方法。在这里，作者发现了一系列小分子二氢乳清酸脱氢酶（DHODH）抑制剂，它们与常见的mdm 2抑制剂nutlin协同作用，增加p53合成并减少肿瘤生长。
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. Activation of the tumor suppressor p53 is a promising approach in cancer therapy. Here, the authors discover a series of small molecule dihydroorotate dehydrogenase (DHODH) inhibitors that increase p53 synthesis and reduce tumor growth in synergy with the common mdm2 inhibitor nutlin3.
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影响因子：
6.7
作者：
Lucas-Hourani M;Dauzonne D;Jorda P;Cousin G;Lupan A;Helynck O;Caignard G;Janvier G;André-Leroux G;Khiar S;Escriou N;Desprès P;Jacob Y;Munier-Lehmann H;Tangy F;Vidalain PO
通讯作者：
Vidalain PO
影响因子：
3
作者：
Reisman D;Takahashi P;Polson A;Boggs K
通讯作者：
Boggs K
影响因子：
4.3
作者：
Loffler, M;Jockel, J;Becker, C
通讯作者：
Becker, C
影响因子：
28.2
作者：
Mathur D;Stratikopoulos E;Ozturk S;Steinbach N;Pegno S;Schoenfeld S;Yong R;Murty VV;Asara JM;Cantley LC;Parsons R
通讯作者：
Parsons R
影响因子：
50.3
作者：
Li L;Wang L;Li L;Wang Z;Ho Y;McDonald T;Holyoake TL;Chen W;Bhatia R
通讯作者：
Bhatia R