PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy.
PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy.
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DOI：
10.1186/s12943-022-01707-5
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发表时间：
2023-03-30
期刊：
影响因子：
37.3
通讯作者：
Gavande, Navnath S. S.
中科院分区：
文献类型：
--
作者：
Kelm, Jeremy M. M.;Pandey, Deepti S. S.;Malin, Evan;Kansou, Hussein;Arora, Sahil;Kumar, Raj;Gavande, Navnath S. S.
分子靶向癌症治疗大大改善了患者的预后，尽管其有效性的持久性可能有限。对这些疗法的抗性通常与靶癌蛋白的适应性变化有关，其降低了结合亲和力。此外，靶向癌症治疗的武器库缺乏对几种臭名昭著的癌蛋白的覆盖，这些癌蛋白具有抑制剂开发的挑战性特征。降解剂是一种相对较新的治疗方式，其通过劫持细胞蛋白质破坏机制来消耗靶蛋白。降解剂为癌症治疗提供了几个优点，包括对靶蛋白中获得性突变的弹性，增强的选择性，较低的剂量要求，以及消除致癌转录因子和支架蛋白的潜力。在此，我们回顾了蛋白水解靶向嵌合体（PROTAC）的发展，为选定的癌症治疗目标和他们的报告的生物活性。PROTAC设计的药物化学一直是一个具有挑战性的活跃研究领域，但该领域的最新进展将迎来一个合理降解剂设计的时代。
Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these therapies is often related to adaptive changes in the target oncoprotein which reduce binding affinity. The arsenal of targeted cancer therapies, moreover, lacks coverage of several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality which deplete the target protein by hijacking the cellular protein destruction machinery. Degraders offer several advantages for cancer therapy including resiliency to acquired mutations in the target protein, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins. Herein, we review the development of proteolysis targeting chimeras (PROTACs) for selected cancer therapy targets and their reported biological activities. The medicinal chemistry of PROTAC design has been a challenging area of active research, but the recent advances in the field will usher in an era of rational degrader design.
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影响因子：
64.8
作者：
Alfieri, Claudio;Chang, Leifu;Zhang, Ziguo;Yang, Jing;Maslen, Sarah;Skehel, Mark;Barford, David
通讯作者：
Barford, David
影响因子：
11.2
作者：
Bai L;Zhou B;Yang CY;Ji J;McEachern D;Przybranowski S;Jiang H;Hu J;Xu F;Zhao Y;Liu L;Fernandez-Salas E;Xu J;Dou Y;Wen B;Sun D;Meagher J;Stuckey J;Hayes DF;Li S;Ellis MJ;Wang S
通讯作者：
Wang S
影响因子：
50.3
作者：
Bai, Longchuan;Zhou, Haibin;Wang, Shaomeng
通讯作者：
Wang, Shaomeng
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：
14.8
作者：
Bondeson DP;Mares A;Smith IE;Ko E;Campos S;Miah AH;Mulholland KE;Routly N;Buckley DL;Gustafson JL;Zinn N;Grandi P;Shimamura S;Bergamini G;Faelth-Savitski M;Bantscheff M;Cox C;Gordon DA;Willard RR;Flanagan JJ;Casillas LN;Votta BJ;den Besten W;Famm K;Kruidenier L;Carter PS;Harling JD;Churcher I;Crews CM
通讯作者：
Crews CM