Targeting transcription factors in cancer - from undruggable to reality.
Targeting transcription factors in cancer - from undruggable to reality.
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DOI：
10.1038/s41568-019-0196-7
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发表时间：
2019-11
期刊：
影响因子：
--
通讯作者：
Bushweller JH
中科院分区：
文献类型：
--
作者：
Bushweller JH
突变或失调的转录因子代表了一类独特的药物靶点，可介导异常基因表达，包括阻断分化和细胞死亡基因表达程序，这是癌症的标志性特征。在许多癌症类型中，转录因子活性通过各种直接机制发生改变，包括染色体易位、基因扩增或缺失、点突变和表达改变，以及通过影响转录因子结合的非编码DNA突变间接改变。在临床前和某些情况下，临床上已经证明了多种靶向转录因子活性的方法，包括抑制转录因子-辅因子蛋白-蛋白质相互作用、抑制转录因子-DNA结合以及通过改变泛素化水平和随后的蛋白酶体降解或通过抑制转录因子表达调节剂来调节转录因子活性水平。此外，最近出现了几种靶向转录因子的新方法，包括调节自身抑制、靶向嵌合体的蛋白水解（PROTAC）、使用半胱氨酸反应性抑制剂、靶向转录因子的内在无序区域以及转录因子抑制剂与激酶抑制剂的组合以阻止耐药性的发展。这些药物开发创新有望产生具有独特特性的药物，这些药物可能会影响未来的癌症治疗。
Mutated or dysregulated transcription factors represent a unique class of drug targets that mediate aberrant gene expression, including blockade of differentiation and cell death gene expression programmes, hallmark properties of cancers. Transcription factor activity is altered in numerous cancer types via various direct mechanisms including chromosomal translocations, gene amplification or deletion, point mutations and alteration of expression, as well as indirectly through non-coding DNA mutations that affect transcription factor binding. Multiple approaches to target transcription factor activity have been demonstrated, preclinically and, in some cases, clinically, including inhibition of transcription factor–cofactor protein–protein interactions, inhibition of transcription factor–DNA binding and modulation of levels of transcription factor activity by altering levels of ubiquitylation and subsequent proteasome degradation or by inhibition of regulators of transcription factor expression. In addition, several new approaches to targeting transcription factors have recently emerged including modulation of auto-inhibition, proteolysis targeting chimaeras (PROTACs), use of cysteine reactive inhibitors, targeting intrinsically disordered regions of transcription factors and combinations of transcription factor inhibitors with kinase inhibitors to block the development of resistance. These innovations in drug development hold great promise to yield agents with unique properties that are likely to impact future cancer treatment.
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影响因子：
4.7
作者：
Carlton AL;Illendula A;Gao Y;Llaneza DC;Boulton A;Shah A;Rajewski RA;Landen CN;Wotton D;Bushweller JH
通讯作者：
Bushweller JH
影响因子：
18.4
作者：
Bhagwat AS;Vakoc CR
通讯作者：
Vakoc CR
影响因子：
7.3
作者：
Borkin D;Klossowski S;Pollock J;Miao H;Linhares BM;Kempinska K;Jin Z;Purohit T;Wen B;He M;Sun D;Cierpicki T;Grembecka J
通讯作者：
Grembecka J
影响因子：
64.8
作者：
Carver, Brett S.;Tran, Jennifer;Chen, Zhenbang;Carracedo-Perez, Arkaitz;Alimonti, Andrea;Nardella, Caterina;Gopalan, Anuradha;Scardino, Peter T.;Cordon-Cardo, Carlos;Gerald, William;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo
DOI：
10.1073/pnas.2035074100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Best, TP;Edelson, BS;Dervan, PB
通讯作者：
Dervan, PB