DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation.
DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation.
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DOI：
10.1126/science.aab1433
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发表时间：
2015-06-19
期刊：
影响因子：
--
通讯作者：
Bradner JE
中科院分区：
文献类型：
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作者：
Winter GE;Buckley DL;Paulk J;Roberts JM;Souza A;Dhe-Paganon S;Bradner JE
小分子拮抗剂使蛋白质靶标的离散生化特性失效。对于多结构域蛋白质靶点，药物作用的药理学结果受到一个结构域特异性活性的选择性破坏的限制。更广泛地说，靶标抑制在动力学上受到靶标接合的持久性和程度的限制。传统药物分子的这些特征对靶向转录因子和染色质相关表观遗传蛋白的抑制剂的开发具有挑战性，这些抑制剂作为多结构域生物分子支架并且通常具有快速缔合和解离动力学。因此，我们设计了一种化学策略，以促进配体依赖性靶蛋白降解，通过化学缀合与衍生的邻苯二甲酰亚胺，劫持的Cereblon E3泛素连接酶复合物的功能。使用这种方法，我们将从染色质（JQ 1）置换BET溴结构域的乙酰基-赖氨酸竞争性拮抗剂转化为邻苯二甲酰亚胺缀合的配体，该配体促进立即的脑蛋白依赖性BET蛋白降解（dBET 1）。表达蛋白质组学证实了在检测的7429种蛋白质中BET家族成员BRD 2、BRD 3和BRD 4的高特异性。与原代人白血病母细胞中的溴结构域抑制相比，BET溴结构域的降解与更快速和更稳健的凋亡反应相关，并且dBET 1在人白血病异种移植物中表现出体内功效。这种方法的范围由降解胞质信号蛋白FKBP 12的第二系列探针说明。总之，这些发现确定了一种简单而通用的新策略来控制靶蛋白的稳定性，并对接近以前难以处理的蛋白质靶点产生了影响。
Small-molecule antagonists disable discrete biochemical properties of protein targets. For multi-domain protein targets, the pharmacologic consequence of drug action is limited by selective disruption of one domain-specific activity. More broadly, target inhibition is kinetically limited by the durability and degree of target engagement. These features of traditional drug molecules are challenging to the development of inhibitors targeting transcription factors and chromatin-associated epigenetic proteins, which function as multi-domain biomolecular scaffolds and generally feature rapid association and dissociation kinetics. We therefore devised a chemical strategy to prompt ligand-dependent target protein degradation, via chemical conjugation with derivatized phthalimides that hijack the function of the Cereblon E3 ubiquitin ligase complex. Using this approach, we converted an acetyl-lysine competitive antagonist that displaces BET bromodomains from chromatin (JQ1) to a phthalimide-conjugated ligand that prompts immediate Cereblon-dependent BET protein degradation (dBET1). Expression proteomics confirms high specificity for BET family members BRD2, BRD3 and BRD4 among 7429 proteins detected. Degradation of BET bromodomains is associated with a more rapid and robust apoptotic response compared to bromodomain inhibition in primary human leukemic blasts, and dBET1 exhibits in vivo efficacy in a human leukemia xenograft. The reach of this approach is illustrated by a second series of probes that degrade the cytosolic signaling protein, FKBP12. Together, these findings identify a facile and general new strategy to control target protein stability, with implications for approaching previously intractable protein targets.