Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas
Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas
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PROTAC 降解 Bruton 酪氨酸激酶突变体可用于治疗依鲁替尼耐药的非霍奇金淋巴瘤
DOI：
10.1038/s41375-019-0440-x
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发表时间：
2019-03
期刊：
影响因子：
11.4
通讯作者：
Yu Rao
中科院分区：
文献类型：
--
作者：
Yonghui Sun;Ning Ding;Yuqin Song;Zimo Yang;Wanli Liu;Jun Zhu;Yu Rao
弥漫性大B细胞淋巴瘤(DLBCL)是最常见的非霍奇金淋巴瘤(NHL)。在美国和英国，DLBCL的年患病率高达0.08%[1]。DLBCL的一线临床治疗是联合化疗和免疫治疗，老年人的5年存活率约为58%[2]。套细胞淋巴瘤(MCL)占全世界NHL的6-8%以上[3]。由于t(11；14)(q13；q32)染色体易位和细胞周期蛋白D1表达上调，MCL常可见恶性增殖[4]。不幸的是，MCL没有最佳的治疗方法[5]，美国MCL患者的5年存活率为50%[6]。这些统计数据表明，迫切需要为DLBCL或MCL患者开发更有效的治疗方法。B细胞受体(BCR)信号对B细胞的黏附、存活和生长是不可或缺的。作为bcr途径中重要的膜近端信号分子，Bruton酪氨酸激酶(BTK)在B细胞的激活和增殖中起着关键作用[7]。2013年，BTK共价抑制剂伊布鲁替尼被美国食品和药物管理局批准用于治疗MCL。此外，活化的B细胞样细胞(ABC)-DLBCL患者在接受伊布鲁替尼治疗后获得缓解[8]。不幸的是，在伊布鲁替尼治疗期间，从MCL患者中分离出了耐药肿瘤细胞，而复发特异的C481S错义BTK突变导致了这种耐药性[9]。在对DLBCL的生长抑制中，BTK C481S突变体也导致了对伊布鲁替尼的耐药性[10]。蛋白水解靶向嵌合体(PROTAC)是一种通过小分子选择性击倒靶蛋白的新策略[11]。PROTAC分子是具有三种成分的异双功能化合物：靶蛋白结合部分、E3连接酶配体和连接两者的连接物(图1A)。降解机制将目标细胞蛋白带到相应的E3连接酶，导致泛素蛋白酶体系统的降解。近年来，这种新发展的方法被广泛应用于抗肿瘤研究[12，13]。最近，我们开发了第一个PROTAC衍生降解剂，用于选择性降解BTK[10，14，15]。虽然初步数据显示我们的降解物在体外有效地控制了BTK C481S突变诱导的伊布鲁替尼耐药B细胞恶性肿瘤，但以下关键问题仍然没有得到解决。(1)BTK降解物在体内对DLBCL也有效吗？由于我们的第一代降解剂的水溶解性较差，必须开发具有更好的溶解性的新一代BTK降解剂用于体内
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). In the United States and United Kingdom, the annual prevalence of DLBCL is as high as 0.08%[1]. The first-line clinical treatment for DLBCL is combined chemo-immunotherapy with a 5-year survival rate of around 58% for senior adults [2]. Mantle cell lymphoma (MCL) contributes to more than 6–8% of NHL worldwide [3]. Because of the t (11; 14)(q13; q32) chromosomal translocation and upregulated expression of cyclin D1, malignant proliferation is commonly observed in MCL [4]. Unfortunately, there is no optimal therapy for MCL [5] and the 5-year survival rate for MCL patients in the United States is< 50%[6]. These statistics highlight an urgent need for the development of more effective treatments for patients with DLBCL or MCL. B-cell receptor (BCR) signaling is indispensable for the adhesion, survival, and growth of B cells. As an essential membrane proximal signal molecule in the BCR pathway, Bruton’s tyrosine kinase (BTK) plays a critical role in B-cell activation and proliferation [7]. In 2013, the BTK covalent inhibitor ibrutinib was approved by the Food and Drug Administration for the treatment of MCL. Additionally, activated B-cell-like (ABC)-DLBCL patients achieved remission after treatment with ibrutinib [8]. Unfortunately, drug-resistant tumor cells have been isolated from MCL patients during treatment with ibrutinib and the relapsespecific C481S missense BTK mutation contributes to this resistance [9]. In the growth inhibition of DLBCL, the BTK C481S mutant also resulted in resistance to ibrutinib [10]. Proteolysis-targeting chimera (PROTAC) is a novel strategy for selective knockdown of target proteins by small molecules [11]. PROTAC molecules are heterobifunctional compounds with three components: a target protein-binding moiety, an E3 ligase ligand, and a linker connecting the two (Fig. 1a). The degradation machinery brings the target cellular protein to the corresponding E3 ligase, resulting in degradation by the ubiquitinproteasome system. In recent years, this newly developed method has been widely used in antitumor studies [12, 13]. Recently, we developed the first PROTAC-derived degrader for selective BTK degradation [10, 14, 15]. Although preliminary data showed that our degrader effectively controlled BTK C481S mutant-induced ibrutinib-resistant B-cell malignancies in vitro, the following critical questions remain unaddressed.(1) Is the BTK degrader also effective for DLBCL in vivo? Due to the poor aqueous solubility of the first generation of our degrader, a new generation of BTK degraders with improved solubility must be developed for in vivo
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影响因子：
20.3
作者：
Liu, Ta-Ming;Woyach, Jennifer A.;Johnson, Amy J.
通讯作者：
Johnson, Amy J.
DOI：
10.1073/pnas.1803662115
发表时间：
2018-07-31
影响因子：
11.1
作者：
Zorba, Adelajda;Chuong Nguyen;Calabrese, Matthew F.
通讯作者：
Calabrese, Matthew F.
DOI：
10.1056/nejmoa1306220
发表时间：
2013-08-08
期刊：
The New England journal of medicine
影响因子：
--
作者：
Wang ML;Rule S;Martin P;Goy A;Auer R;Kahl BS;Jurczak W;Advani RH;Romaguera JE;Williams ME;Barrientos JC;Chmielowska E;Radford J;Stilgenbauer S;Dreyling M;Jedrzejczak WW;Johnson P;Spurgeon SE;Li L;Zhang L;Newberry K;Ou Z;Cheng N;Fang B;McGreivy J;Clow F;Buggy JJ;Chang BY;Beaupre DM;Kunkel LA;Blum KA
通讯作者：
Blum KA
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
20.3
作者：
Morton, LM;Wang, SS;Linet, MS
通讯作者：
Linet, MS