Rational optimization of a transcription factor activation domain inhibitor.
Rational optimization of a transcription factor activation domain inhibitor.
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转录因子激活结构域抑制物的合理优化。
DOI：
10.1038/s41594-023-01159-5
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发表时间：
2023-12
影响因子：
16.8
通讯作者：
Salvatella, Xavier
中科院分区：
文献类型：
--
作者：
Basu, Shaon;Martinez-Cristobal, Paula;Frigole-Vivas, Marta;Pesarrodona, Mireia;Lewis, Michael;Szulc, Elzbieta;Banuelos, C. Adriana;Sanchez-Zarzalejo, Carolina;Bielskute, Stase;Zhu, Jiaqi;Pombo-Garcia, Karina;Garcia-Cabau, Carla;Zodi, Levente;Dockx, Hannes;Smak, Jordann;Kaur, Harpreet;Batlle, Cristina;Mateos, Borja;Biesaga, Mateusz;Escobedo, Albert;Bardia, Lidia;Verdaguer, Xavier;Ruffoni, Alessandro;Mawji, Nasrin R.;Wang, Jun;Obst, Jon K.;Tam, Teresa;Brun-Heath, Isabelle;Ventura, Salvador;Meierhofer, David;Garcia, Jesus;Robustelli, Paul;Stracker, Travis H.;Sadar, Marianne D.;Riera, Antoni;Hnisz, Denes;Salvatella, Xavier
转录因子是最有吸引力的治疗靶点之一，但在很大程度上被认为是“不可用药的”，部分原因是它们的活化域本质上是无序的。在这里，我们展示了雄激素受体激活域的芳香特性，雄激素受体是抗去势前列腺癌的治疗靶点，是其作为转录因子活性的关键，使其在被雄激素激活时能够移位到细胞核并划分为转录缩合物。基于我们对稳定这种缩合物的相互作用和结构域在缩合时采用的理解，我们优化了以前通过表型筛选鉴定的小分子抑制剂的结构。优化后的化合物更接近其靶标，抑制雄激素受体依赖的转录程序，并在细胞内和体内的去势抵抗前列腺癌模型中具有抗肿瘤作用。这些结果表明，有可能合理地优化，甚至有可能设计以致癌转录因子的激活区域为靶点的小分子。转录因子具有丰富的内在紊乱，因此很难用药。作者通过了解雄激素受体的激活域如何激活转录，改进了一种治疗去势抵抗前列腺癌的实验药物。
Transcription factors are among the most attractive therapeutic targets but are considered largely ‘undruggable’ in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening. The optimized compounds had more affinity for their target, inhibited androgen-receptor-dependent transcriptional programs, and had an antitumorigenic effect in models of castration-resistant prostate cancer in cells and in vivo. These results suggest that it is possible to rationally optimize, and potentially even to design, small molecules that target the activation domains of oncogenic transcription factors. Transcription factors are rich in intrinsic disorder and therefore hard to drug. The authors improve an experimental drug for castration-resistant prostate cancer by learning how the activation domain of the androgen receptor activates transcription.
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影响因子：
50.3
作者：
Cato, Laura;de Tribolet-Hardy, Jonas;Brown, Myles
通讯作者：
Brown, Myles
影响因子：
64.5
作者：
Basu, Shaon;Mackowiak, Sebastian D.;Hnisz, Denes
通讯作者：
Hnisz, Denes
影响因子：
50.3
作者：
Andersen, Raymond J.;Mawji, Nasrin R.;Sadar, Marianne D.
通讯作者：
Sadar, Marianne D.
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J
影响因子：
64.5
作者：
Boija A;Klein IA;Sabari BR;Dall'Agnese A;Coffey EL;Zamudio AV;Li CH;Shrinivas K;Manteiga JC;Hannett NM;Abraham BJ;Afeyan LK;Guo YE;Rimel JK;Fant CB;Schuijers J;Lee TI;Taatjes DJ;Young RA
通讯作者：
Young RA