CN113768911A - Apobec3b抑制剂及其应用 - Google Patents
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Abstract
本发明提供了一种式Ⅰ的APOBEC3B的小分子抑制剂，其可以通过抑制APOBEC3B的脱氨酶功能，降低突变负荷，能有效预防和治疗过度表达APOBEC3B的癌症。该化合物安全性高，价格低廉，具有良好的应用前景。
Description
技术领域：
本发明属于医药技术领域，具体涉及载脂蛋白B mRNA催化性多肽3B(APOBEC3B)的小分子抑制剂及其在制备癌症预防和治疗药物中的应用。
背景技术：
流行病学研究表明，饮酒、吸烟、从饮食中接触致癌物和微量营养素缺乏等外源性因素均能促进癌症的发生与发展。虽然一些化学预防药物，如膳食补充剂，已被用于预防食管鳞癌的发展，但由于治疗靶点和机制尚不明确，其总体效益仍存在争议。另一方面，大量的二代测序结果显示，绝大多数的人类癌症是由体细胞突变积累引起的，DNA损伤和突变将导致基因组不稳定，也是癌症中主要的单碱基替换特征。因此，针对DNA突变驱动靶点开发癌症预防和治疗药物，对于防治癌症的发生和发展具有重要的临床意义。
载脂蛋白B mRNA催化性多肽(APOBEC)家族包括11个成员，其中APOBEC3B在多种肿瘤中高表达，且是除年龄因素外的第二位内源性突变驱动者。APOBEC3B的过度表达通过作用于DNA损伤或复制叉中断所产生的单链DNA(ssDNA)，引起胞嘧啶脱氨形成尿嘧啶，产生C>T突变和C>G突变，产生大量体细胞突变，进而引起癌变。
发明内容
本发明通过计算机辅助筛选和体内外活性实验，鉴定获得了靶向APOBEC3B的式I的小分子抑制剂
其中R1选自F、Cl或I，R2选自I或H，R3选自取代或未取代的羟基或氨基，R4选自H、卤素、巯基、羟基或氨基。本发明的APOBEC3B抑制剂，能够降低由APOBEC3B脱氨作用引起的大量体细胞突变。式Ⅰ化合物R3所连C原子的构型为R型或S型，优选为S型。
进一步地，所述式Ⅰ化合物能够显著抑制体内肿瘤生长，减小肿瘤体积，降低突变数量，且对体内脏器无显著毒副作用。
进一步的，所述的癌症为实体瘤，包括但不限于食管鳞癌、乳腺癌、结肠癌、头颈部鳞状细胞癌、***、卵巢癌、子宫内膜癌、肺癌、胃癌、肝癌、肾癌、膀胱癌、***癌。
优选地，式I化合物为3,5-二碘酪氨酸：
本发明公开了式I或其药学上可接受的盐、其类似物预防和/或治疗高表达APOBEC3B导致的癌症。
本发明式I可通过购买或常规工艺得到，比如从海带中提取或人工合成。在一个实施方案中，本发明公开了含式I的药物。
1.进一步地，所述药物的剂型为任何药物治疗学上可接受的剂型。
2.进一步地，所述药物的剂量为任何药物治疗学上可接受的剂量。
3.具体而言，所述药物的剂型包含但不限于片剂、颗粒剂、胶囊剂、散剂、丸剂、口服液、注射用粉针剂、注射液、透皮贴剂、凝胶剂、软膏剂。
附图说明
图1为生理盐水，500μg/kg和2mg/kg剂量的3,5-二碘酪氨酸对4-NQO诱导建立的自发性食管鳞癌小鼠肿瘤生长的抑制作用，包括肿瘤结节长径和肿瘤结节数量的统计结果图；
图2为生理盐水组与500μg/kg的3,5-二碘酪氨酸组食管鳞癌小鼠的食管组织外显子组中突变数量的统计结果图。
具体实施方式
实施例1：APOBEC3B抑制剂的筛选与结构
通过Protein Data Bank(PDB)数据库，搜索得到APOBEC3B的蛋白晶体结构“5TD5”，并根据配体结合区域确定APOBEC3B的酶活性位置并将其作为对接口袋。
应用计算机辅助药物筛选方法通过分子对接方式得到与APOBEC3B高亲和性和结合稳定性的APOBEC3B抑制剂。利用分子模拟药物设计软件Molecular OperationEnvironment(MOE)将源于天然产物数据库中的638个小分子化合物与APOBEC3B进行分子对接，根据打分值(S<-7)与五大类药性原则，最终筛选得到与APOBEC3B具有较好亲和力的30个候选化合物进行实验验证。
实施例2：APOBEC3B小分子抑制剂的体外酶活性抑制研究
上述计算机虚拟筛选得到的候选化合物通过荧光标记的DNA胞嘧啶脱氨酶法，得到3,5-二碘酪氨酸及其类似物能够高亲和APOBEC3B并呈现剂量梯度效应。具体实施方法如下：
1)小分子化合物用DMSO分别稀释到10mM，用含50mM Tris-Cl、150mM NaCl，1mMPMSF的蛋白稀释液分别倍比稀释得到(100μM,10μM,1μM,0.1μM,0.01μM,0.001μM)6个浓度梯度的样品，各取10μL到384孔板中，对照孔中加入等体积稀释液；
2)每孔加入15μL的0.04μM的APOBEC3B蛋白，在酶标板摇床上混合摇动1min后，放置于37℃培养箱孵育15min；
3)分别取15μL的0.5μM ssDNA底物，0.03unit的尿嘧啶糖基化酶(UDG)到上述混合液中，酶标板上摇1min后，放置于37℃培养箱孵育2h进行反应；
4)5μL的4M NaOH加入反应体系，酶标板上方摇1min，37℃培养箱孵育30min；
5)将40μL终止液(35μL 2M Tris-Cl(PH7.9)+5μL 4M HCl)加入上述反应体系中终止反应，置于室温酶标板摇动3min；
6)384孔板置于酶标仪中，在490nm激发光和520nm发射光下检测荧光强度。统计方法：实验结果用均数±标准差(means±SD)表示。
实验结果：
实施例3：为进一步验证本发明化合物能够抑制APOBEC3B发挥胞嘧啶脱氨酶活性，进行了细菌组重测序，具体实施方法如下：
1)构建原核表达载体：将APOBEC3B全长序列***原核载体pET-28a序列中；
2)将上述原核表达载体转入大肠杆菌BL21中；
3)挑取单克隆，在LB培养基中扩培，用Vehicle和3,5-二碘酪氨酸处理并培养菌液3天，同时加入锌离子；
4)提取细菌基因组DNA进行细菌组重测序分析。
实验结果：细菌重测序结果表明，3,5-二碘酪氨酸处理细菌后，APOBEC3B所特有的C>T单碱基变异数量显著降低。
实施例4：抗肿瘤活性体内研究
1)实验材料
试剂：
4-硝基喹啉-1-氧化物(4-NQO)、生理盐水、3,5-二碘酪氨酸
2)实验动物
6周龄C57BL/6J雌鼠，SPF级，购于北京维通利华生物科技股份有限公司。实验动物全程无菌饲养，自由摄食饮水。所用笼具、饲料、垫料、以及饮水均经过高压灭菌消毒，饲养环境符合医学实验动物环境设施要求。
食管鳞癌小鼠模型：购买后的小鼠在实验动物中心适应性饲养一周后，开始饲喂配制好的含100μg/mL 4-NQO的饮用水(置于避光饮用瓶)，持续饲喂16周后，改为正常无菌饮用水继续自发诱导形成食管鳞癌小鼠。诱导的第28周，将小鼠随机分为两组，将生理盐水，500μg/kg和2mg/kg的3,5-二碘酪氨酸以腹腔给药方式进行给药，隔天使用电子天平测量小鼠体重，两天给药一次，14天后牺牲小鼠，进行后续实验。统计方法：组间比较采用t检验(*p<0.05，**p<0.01，***p<0.001)。
4-NQO诱导的食管鳞癌小鼠抑瘤实验表明，3,5-二碘酪氨酸能够有效抑制食管鳞癌肿瘤生长，并且通过靶向APOBEC3，降低外显子组中的突变负荷，抑制食管鳞癌的进展，达到有效的预防效果，结果如图1和图2所示。
最后应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (9)
1.下述式Ⅰ化合物或其药学上可接受的盐在制备APOBEC3B抑制剂中的应用，其中R1选自F、Cl或I，R2选自I或H，R3选自取代或未取代的羟基或氨基，R4选自H、卤素、巯基、羟基或氨基。
2.如权利要求1所述的应用，其特征是，所述R1、R2选自如下组合：
3.如权利要求1或2所述的应用，其特征是，所述R3选自氨基或R5-C(O)-取代的羟基或氨基，优选R5为H或卤素，更优选R3选自氨基或HC(O)-NH-。
4.如权利要求1或2所述的应用，其特征是，所述R4选自H或羟基。
5.如权利要求1所述的应用，其特征是，式Ⅰ化合物选自如下化合物：
6.如任一在先权利要求所述的应用，其特征是，式Ⅰ化合物R3所连C原子的构型为R型或S型，优选为S型。
7.如权利要求1所述的应用，其特征是，式Ⅰ化合物为
8.如权利要求1所述的应用，其特征是，所述抑制剂用于预防和/或治疗过度表达APOBEC3B的癌症，优选所述癌症为实体瘤。
9.如权利要求1所述的应用，其特征是，所述抑制剂用于预防和/或治疗结肠癌、头颈部鳞状细胞癌、***、卵巢癌、子宫内膜癌、肺癌、胃癌、肝癌、肾癌、膀胱癌、***癌或食管鳞癌。
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