Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway.
Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway.
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DOI：
10.1186/s10020-022-00537-x
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发表时间：
2022-09-07
影响因子：
5.7
通讯作者：
Liu, Yong
中科院分区：
文献类型：
--
作者：
Wang, Bingwu;Gao, Jian;Zhao, Zhongjun;Zhong, Xuefei;Cui, Hao;Hou, Hui;Zhang, Yanping;Zheng, Junnian;Di, Jiehui;Liu, Yong
靶向核糖体生物合成以激活p53最近已成为人类癌症的治疗策略。在各种核糖体蛋白中，RPL 11通过结合MDM 2集中核仁应激传感途径，导致MDM 2失活和p53激活。因此，MDM 2结合RPL 11模拟物的鉴定对于抗癌治疗是有价值的。基于RPL 11和MDM 2之间界面的晶体结构，我们通过虚拟筛选鉴定了15个潜在的MDM 2变构调节剂。这些化合物之一，命名为S9，直接结合MDM 2并竞争性抑制RPL 11和MDM 2之间的相互作用，导致p53稳定和活化。此外，S9在体外和体内抑制癌细胞增殖。机制研究表明，MDM 2是S9诱导的G2期细胞阻滞和凋亡所必需的，而p53则参与了S9诱导的凋亡。总之，S9可以作为开发特异性靶向RPL 11-MDM 2-p53通路的抗癌药物的先导化合物。在线版本包含补充材料，可通过10.1186/s10020-022-00537-x获得。
Targeting ribosome biogenesis to activate p53 has recently emerged as a therapeutic strategy in human cancer. Among various ribosomal proteins, RPL11 centralizes the nucleolar stress-sensing pathway by binding MDM2, leading to MDM2 inactivation and p53 activation. Therefore, the identification of MDM2-binding RPL11-mimetics would be valuable for anti-cancer therapeutics. Based on the crystal structure of the interface between RPL11 and MDM2, we have identified 15 potential allosteric modulators of MDM2 through the virtual screening. One of these compounds, named S9, directly binds MDM2 and competitively inhibits the interaction between RPL11 and MDM2, leading to p53 stabilization and activation. Moreover, S9 inhibits cancer cell proliferation in vitro and in vivo. Mechanistic study reveals that MDM2 is required for S9-induced G2 cell cycle arrest and apoptosis, whereas p53 contributes to S9-induced apoptosis. Putting together, S9 may serve as a lead compound for the development of an anticancer drug that specifically targets RPL11-MDM2-p53 pathway. The online version contains supplementary material available at 10.1186/s10020-022-00537-x.
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影响因子：
50.3
作者：
Macias E;Jin A;Deisenroth C;Bhat K;Mao H;Lindström MS;Zhang Y
通讯作者：
Zhang Y
DOI：
10.1073/pnas.1303002110
发表时间：
2013-09-03
影响因子：
11.1
作者：
Chang, Yong S.;Graves, Bradford;Sawyer, Tomi K.
通讯作者：
Sawyer, Tomi K.
抑制RNA聚合酶I作为促进p53癌症特异性激活的治疗策略。
影响因子：
50.3
作者：
Bywater MJ;Poortinga G;Sanij E;Hein N;Peck A;Cullinane C;Wall M;Cluse L;Drygin D;Anderes K;Huser N;Proffitt C;Bliesath J;Haddach M;Schwaebe MK;Ryckman DM;Rice WG;Schmitt C;Lowe SW;Johnstone RW;Pearson RB;McArthur GA;Hannan RD
通讯作者：
Hannan RD
影响因子：
8
作者：
Giono LE;Resnick-Silverman L;Carvajal LA;St Clair S;Manfredi JJ
通讯作者：
Manfredi JJ
DOI：
10.1016/j.bbagrm.2012.10.014
发表时间：
2013-03
影响因子：
4.7
作者：
Hannan, K. M.;Sanij, E.;Rothblum, L. I.;Hannan, R. D.;Pearson, R. B.
通讯作者：
Pearson, R. B.