Chemically induced proximity in biology and medicine.
Chemically induced proximity in biology and medicine.
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DOI：
10.1126/science.aao5902
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发表时间：
2018-03-09
期刊：
影响因子：
--
通讯作者：
Crabtree GR
中科院分区：
文献类型：
--
作者：
Stanton BZ;Chory EJ;Crabtree GR
邻近性，或分子的物理接近性，是生物学中普遍存在的调节机制。例如，大多数翻译后修饰，如磷酸化，甲基化和乙酰化，促进分子的接近，在细胞过程中发挥决定性作用。为了理解邻近性在生物机制中的作用，开发了邻近性化学诱导物（CIP）来综合模拟生物调节的募集。化学诱导的邻近允许转录、信号级联、染色质调节、蛋白质折叠、定位和降解以及许多其他生物过程的精确时间控制。对基础研究中CIP的系统分析，加上利用CRISPR的最新技术进步，区分了因果关系与巧合的作用，并允许在合成生物学中进行数学建模。最近，诱导邻近提供了基因治疗的新途径和癌症治疗的新进展。化学诱导的接近。(Top)左：小分子（六边形）结合感兴趣的蛋白质（新月形），使其二聚化以增加反应的有效摩尔浓度。[A]单体蛋白和[AB*]二聚体浓度;箭头，位置坐标。中间：合成二聚体标记蛋白质（蓝色圆圈）用于蛋白酶体降解（红色棒）。右图：同源二聚化分子形成细胞凋亡的“死亡开关”。（底部）CIP模拟细胞过程。左：蛋白质运输机制-核输入和输出，膜融合和蛋白质折叠。中位：通过与DNA或染色质结合（带白色链的球体），通过募集转录激活因子或抑制因子（蓝色和红色箭头）来调节基因激活。右图：信号转导通路。自然界已经进化出了优雅的机制来调节分子之间的物理距离，或接近度，用于各种各样的目的。无论是细胞膜受体的激活，神经元通过突触的传递，还是细菌生物膜中的群体感应，邻近都是生物学中普遍存在的调节机制。在过去的二十年里，化学诱导的邻近性已经揭示了许多基本特征和过程，包括蛋白质结构、染色体结构、染色质可及性、转录和细胞信号传导，都受分子邻近性的支配。我们回顾了化学诱导剂（CIP）的重要进展，这些进展为生物学研究的活跃领域提供了信息，从基本进展到细胞和分子治疗的发展。直到20世纪90年代，人们还不清楚邻近性是否足以启动信号事件或驱动它们对转录的影响。合成小分子诱导的T细胞受体二聚化提供了第一个证据，表明邻近性可以用来理解信号转导。小分子诱导邻近系统的一个显著特征（与典型的敲除或敲除方法相比）是能够在中途启动过程并通过精确的时间控制辨别随后的事件顺序。诱导邻近的快速可逆性使得能够精确分析细胞和表观遗传记忆，并能够构建合成的调节回路。将CRISPR-Cas技术整合到CIP策略中，扩大了这些技术的范围，可以在任何基因背景下，在任何基因座，在几分钟的时间尺度上研究基因调控。此外，CIP已被用于剖析似乎很好理解的过程，从高尔基体和内质网之间的蛋白质运输突触小泡传输的机制。最近的进展，在邻近诱导的细胞凋亡，抑制聚集，内源性蛋白质的选择性降解可能会产生新的类药物在不久的将来。我们回顾了基本的概念进展，使合成的接近以及新兴的CIP为基础的治疗方法。精确调控和完全人源化系统的基因治疗现在是可能的。通过半胱天冬酶活化的基于邻近的细胞凋亡与嵌合抗原受体（CAR）T细胞疗法的整合提供了安全开关，使得能够减轻来自工程化免疫细胞的并发症，例如移植物抗宿主病和B细胞再生障碍。此外，这种整合促进了成功移植后患者细胞再增殖的潜力。随着诺华公司最近批准的一种CAR T细胞治疗药物CTL 019，涉及使用基于CIP的安全开关的综合策略正在出现。创新范例包括BPX-601（NCT 02744287）和BPX-701（NCT 02743611），目前正处于1期临床试验。通过使用类似的基于邻近性的方法，条件性小分子蛋白质降解剂也有望具有广泛的临床用途。该方法使用双功能小分子通过与E3泛素连接酶二聚化来降解致病蛋白。二聚化降解策略特别具有开创性，因为它们能够重新利用与其致病蛋白紧密结合但以前可能没有提供直接治疗效果的任何化学探针。我们预计，通过人源化基因疗法和二聚降解方法翻译CIP方法将产生深远的临床影响。
Proximity, or the physical closeness of molecules, is a pervasive regulatory mechanism in biology. For example, most posttranslational modifications such as phosphorylation, methylation, and acetylation promote proximity of molecules to play deterministic roles in cellular processes. To understand the role of proximity in biologic mechanisms, chemical inducers of proximity (CIPs) were developed to synthetically model biologically regulated recruitment. Chemically induced proximity allows for precise temporal control of transcription, signaling cascades, chromatin regulation, protein folding, localization, and degradation, as well as a host of other biologic processes. A systematic analysis of CIPs in basic research, coupled with recent technological advances utilizing CRISPR, distinguishes roles of causality from coincidence and allows for mathematical modeling in synthetic biology. Recently, induced proximity has provided new avenues of gene therapy and emerging advances in cancer treatment. Chemically induced proximity. (Top) Left: Small molecules (hexagons) bind proteins of interest (crescents), dimerizing them to increase the effective molarity of reactions. [A] monomeric protein and [AB*] dimer concentrations; arrows, position coordinates. Middle: Synthetic dimerizers tag proteins (blue circles) for proteasomal degradation (red rods). Right: Homodimerizing molecules form kill switches for apoptosis. (Bottom) CIPs mimic cellular processes. Left: Protein transport mechanisms—nuclear import and export, membrane fusion, and protein folding. Middle: Regulation of gene activation by binding to DNA or chromatin (spheres with white strands), through recruitment of transcriptional activators or repressors (blue and red arrows). Right: Signal transduction pathways. Nature has evolved elegant mechanisms to regulate the physical distance between molecules, or proximity, for a wide variety of purposes. Whether it is activation of cell-membrane receptors, neuronal transmission across the synapse, or quorum sensing in bacterial biofilms, proximity is a ubiquitous regulatory mechanism in biology. Over the past two decades, chemically induced proximity has revealed that many essential features and processes, including protein structure, chromosomal architecture, chromatin accessibility, transcription, and cellular signaling, are governed by the proximity of molecules. We review the critical advances in chemical inducers of proximity (CIPs), which have informed active areas of research in biology ranging from basic advances to the development of cellular and molecular therapeutics. Until the 1990s, it was unclear whether proximity was sufficient to initiate signaling events or drive their effect on transcription. Synthetic small molecule–induced dimerization of the T cell receptor provided the first evidence that proximity could be used to understand signal transduction. A distinguishing feature of small-molecule induced-proximity systems (compared to canonical knockdown or knockout methods) is the ability to initiate a process midway and discern the ensuing order of events with precise temporal control. The rapid reversibility of induced proximity has enabled precise analysis of cellular and epigenetic memory and enabled the construction of synthetic regulatory circuits. Integration of CRISPR-Cas technologies into CIP strategies has broadened the scope of these techniques to study gene regulation on time scales of minutes, at any locus, in any genetic context. Furthermore, CIPs have been used to dissect the mechanisms governing seemingly well-understood processes, ranging from transport of proteins between the Golgi and endoplasmic reticulum to synaptic vesicle transmission. Recent advances in proximity-induced apoptosis, inhibition of aggregation, and selective degradation of endogenous proteins will likely yield new classes of drugs in the near future. We review fundamental conceptual advances enabled by synthetic proximity as well as emerging CIP-based therapeutic approaches. Gene therapy with precise regulation and fully humanized systems are now possible. Integration of proximity-based apoptosis through caspase activation with chimeric antigen receptor (CAR) T cell therapies provides a safety switch, enabling mitigation of complications from engineered immune cells, such as graft-versus-host disease and B cell aplasia. Furthermore, this integration facilitates the potential for repopulation of a patient’s cells after successful transplantation. With the recent approval of CTL019, a CAR T cell therapeutic from Novartis, integrated strategies involving the use of CIP-based safety switches are emerging. Innovative exemplars include BPX-601 (NCT02744287) and BPX-701 (NCT02743611), which are now in phase 1 clinical trials. By using a similar proximity-based approach, conditional small-molecule protein degraders are also expected to have broad clinical utility. This approach uses bifunctional small molecules to degrade pathogenic proteins by dimerizing with E3 ubiquitin ligases. Degradation-by-dimerization strategies are particularly groundbreaking, because they afford the ability to repurpose any chemical probe that binds tightly with its pathogenic protein but which may not have previously provided a direct therapeutic effect. We anticipate that the translation of CIP methodology through both humanized gene therapies and degradation-by-dimerization approaches will have far-reaching clinical impact.
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影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
64.8
作者：
Erb MA;Scott TG;Li BE;Xie H;Paulk J;Seo HS;Souza A;Roberts JM;Dastjerdi S;Buckley DL;Sanjana NE;Shalem O;Nabet B;Zeid R;Offei-Addo NK;Dhe-Paganon S;Zhang F;Orkin SH;Winter GE;Bradner JE
通讯作者：
Bradner JE
影响因子：
16.6
作者：
Braun SMG;Kirkland JG;Chory EJ;Husmann D;Calarco JP;Crabtree GR
通讯作者：
Crabtree GR
影响因子：
64.8
作者：
CHEN, JD;EVANS, RM
通讯作者：
EVANS, RM
DOI：
10.1073/pnas.93.10.4604
发表时间：
1996-05-14
影响因子：
11.1
作者：
Belshaw, PJ;Ho, SN;Schreiber, SL
通讯作者：
Schreiber, SL