CN108774219B - 抑制pd-1/pd-l1的小分子化合物及其用途 - Google Patents
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Abstract
本发明公开了化合物或其药学上可以接受的盐或酯或溶剂化合物在制备PD‑1/PD‑L1小分子抑制剂药物中的用途。本发明通过计算机模拟虚拟筛选出化合物库中具有潜在活性的候选分子,运用均相时间分辨荧光技术,对候选分子拮抗PD‑1/PD‑L1结合情况进行高通量筛选,选择活性较好的化合物进行小鼠黑色素瘤B16‑F10植瘤实验,确定本发明筛选的化合物具有抗肿瘤活性。
Description
技术领域
本发明涉及一类化合物或其药学上可以接受的盐或酯或溶剂化合物在制备PD-1/PD-L1抑制剂药物中的用途,属于医药领域。
背景技术
程序性细胞死亡蛋白1(programmed cell deathprotein 1,PD-1)是一种表达于T细胞,并可下调免疫系统功能的Ⅰ型跨膜蛋白,由288个氨基酸构成,包括胞外段的IgV区,跨膜段以及胞内部分。该蛋白的胞内段在免疫受体酪氨酸抑制基序和免疫受体酪氨酸转换基序上存在两个关键的磷酸化位点,其在PD-1发挥抑制T细胞信号转导的过程中起了重要作用。PD-1的天然结合配体为程序性细胞死亡蛋白配体1(programmed death-ligand 1, PD-L1)和程序性细胞死亡蛋白配体2(programmed death-ligand 2,PD-L2),与配体结合后可抑制T细胞产生的免疫应答,降低相关细胞因子的产生。研究表明,PD-1/PD-L1靶点在肿瘤、自身免疫性疾病以及移植排斥等方面均有重要作用。当肿瘤发生时,组织细胞表面的PD-L1表达量上调,产生抑制 T细胞激活的信号,从而介导肿瘤逃逸的发生。目前PD-1/PD-L1抑制剂的开发主要集中在单克隆抗体领域,已有派姆单抗(Pembrolizumab)、纳武单抗(Nivolumab)、阿特珠单抗(Atezolizumab)等药物上市,可用于治疗黑色素瘤、转移性非小细胞肺癌、转移性头颈鳞状上皮细胞癌等恶性肿瘤,并且治疗效果显著。与抗体药物良好的发展现况相比,小分子药物的研发却进展缓慢。因此,亟需一类小分子化合物,用于制备治疗恶性肿瘤的药物。
发明内容
本发明的目的在于提供一类化合物或其药学上可以接受的盐或酯或溶剂化合物,制备PD-1/PD-L1抑制剂药物,用于治疗恶性肿瘤。
本发明结合PD-1/PD-L1共晶结构,通过计算机模拟虚拟筛选出化合物库中具有潜在活性的候选分子,运用均相时间分辨荧光技术,对候选分子拮抗PD-1/PD-L1结合情况进行高通量筛选,选择活性较好的化合物进行深入研究,待测样品库购自美国ChemDiv公司高通量筛选化合物库。
为实现上述目的,本发明采用如下技术方案:
式(Ⅰ)的化合物或其药学上可以接受的盐或酯或溶剂化合物在制备 PD-1/PD-L1小分子抑制剂药物中的用途,
其中,R1为
R2为氢、卤素、1~6个碳的取代或非取代的烷基(如甲基、乙基)、取代或非取代的苄基、取代或非取代的杂芳基亚甲基(如吡啶亚甲基、四氟吡啶亚甲基)、1~6个碳的取代或非取代的烷基氧基(如甲氧基)、氰基(如乙腈)、硝基(如甲硝基)、羧基、酯基(如甲酯基)、氨基、取代氨基(如甲氨基)、羟基、酰胺(如甲酰胺)、磺酰胺(如甲磺酰胺)、取代或非取代的苯甲酰基(如四氟苯甲酰基)、取代或非取代的杂芳基甲酰基(如四氟吡啶)、取代或非取代的苯磺酰基(如四氟苯磺酰基)、取代或非取代的芳基或杂芳基(如三氯苯环)、1~6个碳的烷基砜基或1~6个碳的烷基亚砜基 (如甲砜基)、ArCO(CH2)m-、Ar(CH2)mCO-、ArCOCO-、ArCO(CH2)mCO-、 ArCONH(CH2)m-、ArCOO(CH2)m-、Ar(CH2)mOOC-或Ar(CH2)mNHOC-,其中,Ar为取代或非取代的芳基或杂芳基,m=1~6。
进一步,式(Ⅰ)的化合物或其药学上可以接受的盐或酯或溶剂化合物用于开发以PD-1/PD-L1为靶点的小分子抑制剂。
进一步,式(Ⅰ)的化合物或其药学上可接受的盐或酯或溶剂化合物在制备预防和治疗抗肿瘤药物中的用途。
进一步,所述肿瘤包括血液癌症、神经系统癌症、胃肠癌、食道癌、泌尿系统癌症、肺癌、肝癌和皮肤癌。
进一步,一种药物组合物,含有式(Ⅰ)的化合物或其药学上可接受的盐或酯或溶剂化物,和药学上可接受的载体。
进一步,所述药物组合物为片剂、胶囊、颗粒剂、散剂、糖浆剂、口服液或注射剂。
本发明的有益效果是:本发明通过计算机模拟虚拟筛选出化合物库中具有潜在活性的候选分子,运用均相时间分辨荧光技术,对候选分子拮抗 PD-1/PD-L1结合情况进行高通量筛选,选择活性较好的化合物进行小鼠黑色素瘤B16-F10植瘤实验,确定本发明筛选的化合物具有抗肿瘤活性。
具体实施方式
以下结合实施例对本发明做进一步的详细描述,所举实例只用于解释本发明,并非用于限定本发明的范围。
实施例1
本发明采用商业化PD-1/PD-L1抑制剂筛选试剂盒,其是基于均相时间分辨荧光技术(Homogeneous Time-Resolved Fluorscence,HTRF)开发的高通量试剂盒。主要依靠受激发的稀土金属螯合物释放能量转移到发光基团而产生检测信号。实验中带有标签1的Tag1-PD-1会与带有标签2的 Tag2-PD-L1结合,加入带有螯合了Eu3+的Tag1抗体以及带有发光基团XL665 的Tag2抗体后,抗体将与各自的目标蛋白结合,在没有阻断剂存在的情况下,PD-1与PD-L1相互结合,两个荧光集团相互靠近,发生荧光共振能量转移,一部分能量将从荧光供体Eu3+基团转移至荧光受体XL665基团,并在665nm处产生荧光,而未被转移的能量将在620nm处发出荧光,此信号将作为背景信号而存在。当拮抗剂存在时,PD-1/PD-L1的结合会被抑制,荧光基团之间距离增加则会使得能量转移失败,荧光信号减弱。利用荧光信号强弱,即可反应出化合物对于PD1/PD-L1结合作用的抑制效果。
实验设计如表1所示:
表1实验组别设计
表1所用蛋白及抗体均为试剂盒内试剂,经试剂盒内相应的溶液溶解后配置成工作液后使用。操作时每孔反应体系中溶剂二甲亚砜(DMSO)的终浓度为0.1%,PD-1的反应终浓度为50nM,PD-L1的反应终浓度为5nM。化合物初筛浓度为10μM。采用Graphpad Prism5.0统计分析软件计算活性化合物IC50。
操作步骤如下:
阴性对照、阳性对照和实验组均设置3个重复。
(1)阴性对照在反应孔中加入6μL稀释液,阳性对照在反应孔中加入 2μL稀释液和4μLPD-L1-Tag1,实验组在反应孔中加入2μL化合物和4μL PD-L1-Tag1;
(2)在每个孔中分别加入4μLPD-1-Tag2;
(3)在每个孔中分别加入4μLPD-L1蛋白;
(4)在每个孔中分别加入4μLPD-1蛋白;
(5)室温避光孵育15min;
(6)分别在每个孔中依次加入5μL anti-Tag1-Eu3+和5μL anti-Tag2-XL665;
(7)室温避光孵育1h;
(8)使用Perkin Elmer Envision进行荧光信号检测。
筛选得到的PD-1/PD-L1小分子抑制剂的结构通式如下:
筛选得到的PD-1/PD-L1小分子抑制剂的IC50如表2所示。
表2筛选得到的PD-1/PD-L1小分子抑制剂的IC50
实施例2化合物M355-0148、M355-0149、M355-0152对小鼠黑色素瘤体内的抑瘤效应
Ⅰ、细胞培养
B16-F10细胞在1640完全培养基(含10%FBS)中培养,待细胞处于对数生长期,生长融合度为80%~90%时,胰酶消化传代。
Ⅱ、小鼠黑色素瘤B16-F10植瘤实验
(1)小鼠分组
取生长状态基本一致的小鼠共24只,分为4组,包括对照组、M355-0148、 M355-0149、M355-0152组;以PBS为空白对照,以M355-0148、M355-0149、 M355-0152为药物,给药剂量为20mg/kg,灌胃给药。
(2)小鼠皮内接种黑色素瘤B16-F10细胞
①麻醉小鼠:将装有黑色素瘤B16-F10细胞的EP管颠倒混匀6次,吸取细胞培养液至0.4ml;
②给每只小鼠的两边腹股沟皮内注射B16F10细胞,每边100μl。
(3)小鼠给药方法
植瘤当天记为D0天,D3天开始给药,灌胃给药,20mg/kg/day。D9天开始,用异氟烷将小鼠麻醉,称重,用游标卡尺测量左右两边肿瘤大小。待肿瘤体积约为2000mm3时,停止给药,处死小鼠,终止动物实验。
各组小鼠肿瘤体积比较结果如表3所示,表明本发明筛选得到的化合物M355-0148、M355-0149、M355-0152对肿瘤具有抑制作用。
表3各组小鼠肿瘤体积
注:所有实验结果均用Mean±SD表示。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (6)
2.权利要求1所述的化合物或其药学上可以接受的盐在制备以PD-1/PD-L1为靶点的小分子抑制剂中的应用。
3.权利要求1所述的化合物或其药学上可接受的盐在制备预防和治疗抗肿瘤药物中的用途。
4.根据权利要求3所述的化合物或其药学上可接受的盐在制备预防和治疗抗肿瘤药物中的用途,其特征在于,所述肿瘤为血液癌症、神经系统癌症、胃肠癌、食道癌、泌尿系统癌症、肺癌、肝癌和皮肤癌。
5.一种药物组合物,其特征在于,含有权利要求1所述的化合物或其药学上可接受的盐,和药学上可接受的载体。
6.根据权利要求5所述的一种药物组合物,其特征在于,所述药物组合物为片剂、胶囊、颗粒剂、散剂、口服液或注射剂。
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