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Journal of Organic Chemistry Research
Vol. 10  No. 01 ( 2022 ), Article ID: 49668 , 8 pages
10.12677/JOCR.2022.101002

TBK1的结构以及小分子抑制剂

张敏，周栩筠，高杰克*

浙江师范大学化学与生命科学学院，浙江 金华

收稿日期：2022年3月1日；录用日期：2022年3月17日；发布日期：2022年3月25日

摘要

坦克结合激酶1(Tank-Binding Kinase 1, TBK1)是天然免疫过程的重要调节因子，通过磷酸化干扰素调节因子3(Interferon Regurlartory Factor 3, IRF3)和干扰素调节因子7(Interferon Regurlartory Factor 7, IRF7)可诱导型干扰素和其他促炎细胞因子的产生。TBK1稳态的失调则会导致许多疾病如炎症、自身免疫性疾病、代谢性疾病和癌症的发展。因此，基于TBK1靶点开发新型高效抑制剂可进一步加深我们对于该靶点的认知，并确认其作为药物靶点的有效性。本文就TBK1蛋白结构以及一些有潜力的药物小分子进行综述。

关键词

TBK1，小分子，抑制剂

Structure of TBK1 and Small Molecule Inhibitors

Min Zhang, Xujun Zhou, Jieke Gao

College of Chemistry and Life Science, Zhejiang Normal University, Jinhua Zhejiang

Received: Mar. 1st, 2022; accepted: Mar. 17th, 2022; published: Mar. 25th, 2022

ABSTRACT

Tank-Binding Kinase 1 (TBK1) is an important regulator of the natural immune process, inducing the production of interferon and other pro-inflammatory cytokines through phosphorylation of interferon regurlartory factor 3 (IRF3) and interferon regurlartory factor 7 (IRF7). Dysregulation of TBK1 homeostasis leads to the development of many diseases such as inflammatory/autoimmune diseases, metabolic diseases and cancer. Therefore, the development of novel potent inhibitors based on the TBK1 target could further enhance our understanding of this target. Our knowledge of this target and its effectiveness as a drug target can be further enhanced. In this paper, we review the structure of TBK1 protein and some promising drug small molecules.

Keywords:TBK1, Small Molecular, Inhibitors

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 前言

1.1. TBK1的功能

先天免疫是机体抵御入侵病原体的第一道防线，机体可通过识别病原体的特定成分，并激活适当的免疫反应 [1]。许多先天免疫信号通路都将汇集于TBK1，该蛋白可介导干扰素和炎症基因的表达，而干扰素和炎症基因正是免疫防御的关键介质 [2]。TBK1是IKK家族的非典型成员，在先天免疫系统中起着关键作用。核因子kappa-B激酶(nuclear factor kappa-B, NF-κB)家族包括经典的IKK激酶(IKKα、IKKβ和IKKγ)和非经典的IKK激酶(IKKɛ和TBK1) [3]。TBK1在所有组织中普遍表达，而IKKɛ的表达仅限于特定组织，如淋巴组织、外周血淋巴细胞和胰腺 [4]。

一方面，TBK1激酶通过介导天然免疫和自噬来抵抗和消除入侵的病原体，但另一方面，TBK1介导的天然免疫信号的慢性激活也会启动对宿主的免疫攻击，导致器官损伤和疾病 [5] [6] [7]。研究发现，非经典激酶IKKɛ和TBKl通过促进慢性炎症细胞因子TNF-α和MCP-1等的表达，可增加自身免疫性疾病和肺部炎症疾病的炎症反应，并减少肥胖鼠脂肪细胞中的β-肾上腺素受体对儿茶酚胺的敏感性，降低第二信使cGAMP的水平。通过对激酶的抑制，可减少慢性疾病和肺部疾病的炎症反应，并减少脂肪细胞中慢性炎症因子的表达，改善胰岛素敏感性，减轻体重，起到治疗肥胖和2型糖尿病的作用 [8]。此外，TBK1在维持肿瘤依赖的自噬和癌症免疫耐受方面也起着关键作用，TBK1可通过新的KRAS效应途径RalB-TBK1促进肿瘤生长 [9] [10] [11]。因此，TBK1被认为是治疗肿瘤、炎症性和自身免疫性疾病的潜在靶点，本文就TBK1蛋白的结构及靶向TBK1的小分子抑制剂进行综述。

1.2. TBK1的结构

人TBK1激酶由745个氨基酸组成，包括一个N-末端激酶结构域(kinase domain, KD)、一个泛素样结构域(ubiquitin-like domain, ULD)、一个α-螺旋支架二聚结构域(α-helical scaffold dimerization domain, SDD)和一个C-末端接头结合结构域(C-terminal adaptor-binding domain, CTD) [12]。KD、ULD和SDD之间的广泛相互作用形成了致密的TBK1二聚体。TBK1的KD由N-末端和C-末端小叶组成，在界面上有一个活性的ATP结合位点。激活环上的Ser172是TBK1激酶的磷酸化位点 [13]。一旦TBK1被磷酸化，激酶结构域的αC-螺旋旋转到向内的活性位置，促进αC-螺旋保守的Glu55残基和活性位点Lys38残基之间形成关键的盐桥相互作用。然而，当TBK1处于非活性构象时，激活环被打乱，αC-螺旋定位到ATP结合结构域之外的非活性位置 [14]。在TBK1二聚体的结构中，TBK1的激活主要由反式自磷酸化控制。两个KD限制了TBK1的顺式自磷酸化活性 [15]。在TBK1上游基因STING的C-末端残基中有一个高度保守的PLRT/SD基序，通过直接与TBK1的二聚体界面结合来介导TBK1的招募。进一步分析STING与 TBK1的晶体结构表明，二聚体TBK1与STING的CTT的两个单体结合，每个STING单体同时与两个TBK1单体结合形成2:2的复合物 [16]。2',3'-cGAMP结合cGAS通过形成稳定的寡聚体来启动STING的激活，STING -CTT中的保守PLPLRT/SD蛋白质基序能够二聚体TBK1界面通过疏水作用结合，诱导STINT和TBK1的磷酸化和激活。进一步的募集和磷酸化IRF3和TBK1的导致下游信号成分的参与和I型IFN转录的诱导调控，I-IFN的转录是cGAS-STING-TBK1信号通路启动的标志信号 [14] [16] [17] [18] [19]。此前有研究表明，病毒感染后糖原合成酶激酶3β (Glycogen Synthase Kinase 3β, GSK3β)被招募到TBK1，促进TBK1的Ser172处的自动磷酸化，然后促进抗病毒反应 [20]。此外，Raf激酶抑制蛋白(RKIP)可以被TBK1在Ser109处磷酸化，增强了RKIP与TBK1的相互作用，进而促进了TBK1的自动磷酸化。此外，TBK1 Ser172可以被上游的ULK1 (Unc-51-like autophagy-activating kinase 1)直接磷酸化，这对于维持细胞内能量稳态有着不可忽视的作用 [21]。

2. TBK1抑制剂进展及其研究

由于TBK1的异常调控被报道与诱导抗病毒天然免疫反应和肿瘤的迁移/进展有关，TBK1已被认为是治疗与cGAS-STING-TBK1通路相关的多种疾病的药物靶点。病毒入侵也是TBK1的一个重要激活途径，可能有助于启动并增强宿主的免疫反应抵御病原体入侵。但是，TBK1的不适当激活也导致许多疾病的如自身免疫、癌症和肥胖的进展。因此，TBK1抑制剂将为这些疾病提供潜在的治疗途径。但由于TBK1激酶的特殊性，针对其直接激动剂的开发是一件非常具有挑战性的事情，因此人们一直致力于TBK1抑制剂的筛选和特性研究 [14] [17] [18]。

2.1. BX795氨基嘧啶类小分子TBK1抑制剂

BX795 (IC50 = 6.0 nM)是于2009年报道的最早的TBK1抑制剂(图1)。该化合物最初是作为PDK1 (3 Phosphoinositide Dependent Protein Kinase 1, IC50=111nM)的抑制剂而开发的，但对其他一些激酶也表现出很强的抑制作用，包括IKKε、MLK1-3 (mixed lineage kinase 1-3)和MARK1-4 (AMP-Activated Protein Kinase 1-4)等 [22]。生物实验表明，BX795能抑制革兰氏阳性菌引起的炎症反应和多种耐药的1型单纯疱疹病毒株细胞的感染。此外，BX795还通过诱导细胞凋亡和M期阻滞来抑制口腔鳞状细胞癌(OSCC)的增殖 [23]。同样，BX795能有效地抑制膀胱癌细胞和PDS的增殖和迁移。这一效果也在异种移植的活体小鼠模型中得到证实 [24] [25]。然而，BX795对其他激酶的非靶向作用则限制其进一步发展。通过BX795的进一步优化得到了MRT67307 (TBK1 IC50 = 19.0 nM, IKKε IC50 = 160.0 nM)，它对IKKα、IKKβ等都表现出了良好的选择性 [26] (图1)。带有MRT67307的TBK1的X射线晶体结构表明，它与BX795以类似的模式结合，但与BX795相比与激酶形成的相互作用较少，导致效力降低和脱靶效应减少[13]。

与之类似结构的还有用于治疗骨髓纤维化的JAK1/2激酶抑制剂CYT387 (TBK1 IC50 = 58 nM, IKKɛ IC50 = 42 nM)，该化合物能有效地促进KRAS突变驱动的NSCLC和PDAC动物模型的肿瘤消退，但在临床上遭到了意想不到的失败 [27] [28] (图1)。GSK8612也是是一种高选择性的TBK1抑制剂(pIC50 = 6.8)，该化合物除了具有较高的水溶性和细胞通透性外，还能有效抑制TBK1介导的IRF3磷酸化以及IFNα和IFNβ的产生 [29] (图1)。由于所有这些早期的TBK1抑制剂都带有一个中枢的氨基嘧啶骨架，因此基于该骨架的研究将进一步深化TBK1抑制小分子的理解。

2.2. Amlexanox及其衍生物

Amlexanox (TBK1 IC50 = 0.8 μM, IKKɛ IC50 = 5.8 μM)是一种被批准用于治疗口疮和哮喘的药物，生物研究表明Amlexanox通过增加小鼠的产热作用、改善胰岛素敏感性、减轻体重和脂肪变性来增加能量消耗 [8] [30] (图2)。此外，已有研究发现Amlexanox可通过抑制TBK1/ IKKɛ从而缓解对乙酰氨基酚引起的小鼠肝纤维化和急性肝损伤 [31]。 但Amlexanox的低溶解性和适中的药效限制了其进一步发展，而后对Amlexanox的C3-羧酸和C7-异丙基取代基做了进一步的结构修饰。在类似物中，只有含有C3-羧酸四唑

Figure 1. Aminopyrimidine Structural TBK1 Small Molecule Inhibitors

图1. 氨基嘧啶类结构TBK1小分子抑制剂

取代化合物A2对TBK1 (IC50 = 0.4 μM)和IKKɛ (IC50 = 0.2 μM)有较强的抑制作用，但该化合物的细胞活性较低(图2)。其他类似物中，C7-环己基类似物A3在3T3-L1细胞中产生最高水平的IL-6分泌，但这些化合物都没有起到协同效应。

Figure 2. Amlexanox and its derivatives

图2. Amlexanox及其衍生物

2.3. 基于PROTAC技术的TBK1抑制剂

蛋白水解靶向嵌合体(Proteolysis Targeting Chimeras, PROTAC)是一种近些年来在药物发现领域新兴的热门技术 [32]。双功能分子与配体结合，通过将E3连接酶募集到靶标蛋白上，最后通过泛素–蛋白酶体系统(the ubiquitin-proteasome system, UPS)被蛋白酶体识别并降解。Crews课题组基于该技术选择结合(Kd = 1.3 nM)的TBK1抑制剂2,4-二氨基嘧啶类结构、VHL (Von Hippele Lindau) (IC50 = 0.8 μM)和E3泛素连接酶羟脯氨酸衍生物作为连接模型 [33]。经过优化，得了高效TBK1抑制化合物3i (TBK1 DC50 = 12 nM, Dmax = 96%)，对相关激酶IKKε具有很好的选择性(图3)。通过改变连接接头的长度和调节结合亲和力来改变两种蛋白质之间的有效距离的效果，揭示了PROTAC对TBK1显示出高效力和高选择性的能力。PROTACs的潜力在几个含有野生型或突变型K-RAS的癌细胞中得到进一步证实，TBK1几乎完全降解，对突变型和野生型细胞系的增殖无明显影响。

2.4. 其他小分子TBK1抑制剂

Wang等人报道了一系列咪唑并吡啶类化合物作为TBK1抑制剂，其中代表性化合物A4 (IC50 = 9 nM)显示出增强的疗效和良好的激酶选择性 [34] [35] (图4)。与之结构相似的咪唑并吡啶衍生物AZ3102909 (IC50 = 5 nM)与MEK抑制剂AZD6244协同诱导耐药NRAS突变黑色素瘤细胞凋亡 [36] (图4)。而后发现了一种同样以咪唑并吡啶为骨架的化合物II (IC50 = 13 nM)是一种高效、低毒性的TBK1抑制剂，在小鼠体内对系统性红斑狼疮等自身免疫性疾病有良好的治疗效果 [37] (图4)。同时，该化合物可通过抑制TBK1导致下游AKT信号的减少，进而抑制非小细胞肺癌的癌细胞株生长。Bayer公司报道的苯并咪唑化合物

Figure 3. TBK1 PROTAC

图3. TBK1 PROTAC

Figure 4. Other TBK1 small molecule inhibitors

图4. 其他TBK1小分子抑制剂

BAY985 (IC50 = 2 nM)是一种高选择性的TBK1抑制剂，但其较差的药代动力学特性使其在黑色素瘤小鼠抗肿瘤实验中表现出了较差的抑制活性[39] (图4)。

3. 总结

虽然结构上的特殊性导致目前只有相关抑制调节小分子的研究，但是TBK1作为一个潜在药物靶点在开发治疗各类相关疾病药物方面仍然备受关注。通过抑制TBK1可以有效减缓肿瘤生长、缓解自身免疫症状和消除炎症，针对TBK1抑制剂的进一步研究有望推动TBK1药物的发展。本文就TBK1激酶的结构以及一些潜力的药物小分子进行了综述，为对TBK1的进一步研究提供线索。

文章引用

张 敏,周栩筠,高杰克. TBK1的结构以及小分子抑制剂
Structure of TBK1 and Small Molecule Inhibitors[J]. 有机化学研究, 2022, 10(01): 18-25. https://doi.org/10.12677/JOCR.2022.101002

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