CN116407540A - 药物在预防和治疗her2表达阳性实体瘤中的应用 - Google Patents
药物在预防和治疗her2表达阳性实体瘤中的应用 Download PDFInfo
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Abstract
本发明提供了一种式I化合物或其可药用盐在制备用于预防或治疗HER2表达阳性实体瘤的药物中的用途。式I化合物抑制HER2表达阳性激酶及细胞株试验中,均表现出极显著的抑制肿瘤生长的治疗效果
Description
技术领域
本发明涉及一种药物的新用途,尤其涉及式I化合物、其可药用盐或组合物在制备预防和治疗HER2表达阳性实体瘤中的用途。
背景技术
表皮生长因子受体(Human Epidermal Growth Factor Receptor,HER)家族包括HER1(erbB1,EGFR)、HER2(erbB2,NEU)、HER3(erbB3)及HER4(erbB4),HER家族在细胞生理过程中发挥重要的调节作用。HER2基因的大多数体细胞突变已被证实可激活和驱动肿瘤的发生发展,HER2没有已知的配体,其通过与家族其他成员形成异源二聚体,其他成员的配体通过异二联体相互作用激活EGFR、HER-3或HER-4激酶,经受体磷酸化来激活下游信号传导通路,主要是通过作用于下游的Ras-Raf-Mek-MAPK、PI3K-Akt-mTOR等,进而影响细胞的增殖、细胞周期调控、凋亡、血管生成等过程。
HER2是重要的实体瘤治疗靶点之一,全球已经有多个HER2靶点药物(酪氨酸激酶抑制剂、抗体药物、ADC)被批准用于乳腺癌、胃癌的治疗,已经获批的几种HER2酪氨酸激酶抑制剂(TKIs)和抗体及ADC药物在HER2阳性的多种恶性实体瘤中显示出良好疗效,包括拉帕替尼(Lapatinib)、来那替尼(Neratinib)和曲妥珠单抗Trastuzumab等。但在临床上尚存在未满足的需求,比如细胞抑制活性不够高等,需要提供一种药效更强的HER2靶点药物。
式I化合物最早披露在中国专利CN201510405448.6(发明名称:苯胺嘧啶衍生物及其在制备抗恶性肿瘤药物中的用途)中。
发明内容
本发明的目的在于提供式I化合物、其可药用盐或其组合物在制备预防或治疗HER2表达阳性实体瘤的药物中的用途,为HER2表达阳性实体瘤的预防或治疗提供了新的治疗途径,增加HER2表达阳性实体瘤的药物治疗选择。
本发明的目的可以通过以下技术方案实现:
本发明提供了一种式I化合物、其可药用盐或其组合物在制备治疗或预防HER2表达阳性实体瘤的药物中的用途:
其中,HER2表达阳性实体瘤是指携带HER2基因的一组包括多种恶性肿瘤在内的疾病。
在一些实施方案中,所述的实体瘤包括但不限于乳腺癌、胃癌、胃肠道癌、食管胃结合部癌、肺癌、卵巢癌、膀胱癌、扁桃腺肿瘤、口腔癌、喉肿瘤、脑癌、宫颈癌、结肠癌、直肠癌、结直肠癌、腹膜癌、胆道癌、食道腺癌和食管癌。
在一些实施方案中,所述实体瘤包括实体瘤的脑转移情况。
本发明通过测试式I化合物对HER2激酶、HER2阳性肿瘤细胞株(HCC1569、HCC202、MKN7、NCI-H2170、SK-OV-3、TE-4、UACC-893、UACC-812和ZR-75-30等)的增殖抑制作用证明其对HER2阳性实体瘤具有良好抑制效果。
本发明还提供了一种组合物在制备用于预防或治疗HER2表达阳性实体瘤的药物中的用途,其中所述组合物包含有效量的式I化合物或其可药用盐,以及可药用的载体。
本发明所提供的组合物除式I化合物及其盐外,还包括一种或多种可药用的载体、稀释剂或赋形剂。载体、稀释剂或赋形剂必须与制剂中的其它组分是相容的,并且对其接受者是无害的。
本发明所提供的组合物可用于实体瘤包括且不限于乳腺癌、胃癌、胃肠道癌、食管胃结合部癌、肺癌、卵巢癌、膀胱癌、扁桃腺肿瘤、口腔癌、喉肿瘤、脑癌、宫颈癌、结肠癌、直肠癌、结直肠癌、腹膜癌、胆道癌、食道腺癌和食管癌等的预防与治疗。
本发明所提供的组合物可用于预防或治疗实体瘤的脑转移瘤。
本发明的组合物还可与其他的一种或多种药物(化疗药物和/或靶向药物)联合使用。当采用联合治疗时,治疗剂可以一起给药或分开给药,可采用相同或不同的给药方式。当治疗剂分开给药时,它们可以同时地或以任何顺序给药。式I化合物和/或其它的一种或多种药学活性剂以及给药的相对时间可以为了实现所需的组合疗效而进行选择。
本发明所提供的组合物可以为胶囊、片剂、粉剂、注射液或外用剂。
本发明所提供的式I化合物具有如下有益效果:
激酶测试试验表明式I化合物具有较强的HER2激酶抑制作用;
体外肿瘤细胞增殖抑制实验表明式I化合物对HER2表达阳性肿瘤细胞株表现出较强的抑制作用。
综上所述,本申请所提供的式I化合物、其可药用盐或其组合物治疗或预防HER2表达阳性实体瘤可以取得预料不到的技术效果。
具体实施方式
为了更好地理解本发明的内容,下面结合具体实施例对本发明的技术方案做进一步的说明,但具体的实施方式并不意味着对本发明有任何限制。
式I化合物按照中国专利CN201510405448.6实施例方法制备。
其他药物、试剂或材料市售购得。
实施例1 HER2激酶活性测试
1.实验方法
利用Mobility shift assay方法对化合物的活性进行测试,方法如下:待测化合物溶解在DMSO中,配制成实验最终所需浓度的50x的储存液。化合物测试起始浓度为10μM,2倍稀释,配置10个浓度梯度。将激酶和ATP及Kinase substrate的混合溶液分别用1xKinase buffer配制成2.5倍终浓度的溶液。在已经加有5μL10%DMSO化合物溶液的384孔板的检测孔中加入10μL2.5x的激酶溶液,室温孵育10min。将2.5x的ATP和Kinase substrate混合溶液10μL加入384孔板的检测孔中,28℃恒温孵育指定时间。加入25μL终止检测液停止激酶反应,利用Caliper EZ Reader收集数据。
2.结果计算
采用分析软件拟合量效曲线,得出各个化合物对HER2激酶活性抑制的IC50(nM)值,如下表所示。
表1激酶抑制活性
实施例2式I化合物对HER2表达阳性肿瘤细胞株的增殖抑制作用
HER2表达阳性肿瘤细胞株:HCC1569、HCC202、MKN7、NCI-H2170、SK-OV-3、TE-4、UACC-893、UACC-812和ZR-75-30。
表2试验细胞株
细胞株 | 来源 | 货号 | 基因特征 | 细胞种属 |
UACC-812 | ATCC | CRL-1897 | HER2+ | 乳腺癌 |
HCC1569 | ATCC | CRL-2330 | HER2+ | 乳腺癌 |
HCC202 | ATCC | CRL-2316 | HER2+ | 乳腺癌 |
UACC-893 | ATCC | CRL-1902 | HER2+ | 乳腺癌 |
ZR-75-30 | ATCC | CRL-1504 | HER2+ | 乳腺癌 |
MKN7 | RIKEN | RCB0999 | HER2+ | 胃癌 |
NCI-H2170 | ATCC | CRL-5928 | HER2+ | 肺癌 |
SK-OV-3 | ATCC | HTB-77 | HER2+ | 卵巢癌 |
TE-4 | RIKEN | RCB2097 | HER2+ | 食道癌 |
其他试剂和材料:胎牛血清、MEM培养基、NEAA添加剂、DMEM培养基、RPMI1640培养基、McCoy`5A培养基、Hybricare培养基、人表皮生长因子、青霉素链霉素混合液、CellTiter-Glo、DMSO、谷氨酰胺、EDTA/胰酶和96-well plate。
供试品:式I化合物、Lapatinib、Neratinib。
试验方法:
从培养箱中取出培养好的细胞,吸走上清,5ml胰酶消化后,用10ml培养基终止胰酶的消化作用,转移细胞悬液至15ml离心管中,1000rpm离心5分钟后,用10mL培养基重悬细胞后,吸取1mL培养基,放入Vi-Cell XR测定细胞的数目和活力。根据测得的细胞密度,将细胞稀释成指定密度的细胞悬液。
用电动排枪将配制好的细胞悬液加入到96孔培养板(#3903)中,每孔100μL细胞悬液。放置在37℃/5%二氧化碳培养箱中培养过夜。取出已配制药物母液,室温融化后,1000rpm离心1分钟后混匀。在孔板中加入待测化合物(10μM起始,3倍稀释,双复孔或单孔,10个浓度),用HPD300仪器将药物加到对应孔内,1000rpm离心1分钟后,将培养板放置在培养箱中培养3天。
3天后,取出细胞培养板,置于显微镜下观察细胞密度。取出细胞板在室温放置平衡半小时,加入100μL CTG试剂,在振荡仪上低速振荡2分钟后,用Enspire仪器测板,处理数据。
将检测药物的浓度的Log值作为横坐标,测得的细胞生长抑制率作为纵坐标作图,用EXCEL-XLFIT软件计算各个化合物在细胞株上的IC50。
试验结果表明,式I化合物对多种肿瘤细胞株抑制活性优于目前在售的HER2表达阳性肿瘤治疗药。
表3细胞抑制活性IC50值(μM)
细胞株 | UACC-812 |
式I化合物 | 2.023 |
Laptinib | >10 |
Neratinib | >10 |
表4细胞抑制活性IC50值(μM)
细胞株 | HCC1569 | HCC202 | UACC-893 | ZR-75-30 | MKN7 | NCI-H2170 | SK-OV-3 | TE-4 |
式I化合物 | 2.419 | 0.332 | 0.539 | 0.094 | 0.664 | 0.019 | 1.018 | 0.030 |
Laptinib | 8.704 | 0.771 | 1.133 | 0.194 | 3.075 | 0.039 | 2.967 | 0.085 |
Claims (10)
2.如权利要求1所述的用途,其中,所述的实体瘤包括乳腺癌、胃癌、胃肠道癌、食管胃结合部癌、肺癌、卵巢癌、膀胱癌、扁桃腺肿瘤、口腔癌、喉肿瘤、脑癌、宫颈癌、结肠癌、直肠癌、结直肠癌、腹膜癌、胆道癌、食道腺癌和食管癌。
3.如权利要求2所述的用途,其中,所述实体瘤包括实体瘤的脑转移瘤。
4.如权利要求1至3中任一项所述的用途,其中,所述的药物可与化疗药物或靶向药物联合使用。
5.如权利要求1至3中任一项所述的用途,其中,所述的药物为片剂、胶囊剂、粉剂或注射液的形式。
7.如权利要求6所述的用途,其中,所述的实体瘤包括乳腺癌、胃癌、胃肠道癌、食管胃结合部癌、肺癌、卵巢癌、膀胱癌、扁桃腺肿瘤、口腔癌、喉肿瘤、脑癌、宫颈癌、结肠癌、直肠癌、结直肠癌、腹膜癌、胆道癌、食道腺癌和食管癌。
8.如权利要求7所述的用途,其中,所述实体瘤包括实体瘤的脑转移瘤。
9.如权利要求6至8中任一项所述的用途,其中,所述的药物可与化疗药物或靶向药物联合使用。
10.如权利要求6至8中任一项所述的用途,其中,所述的药物为片剂、胶囊剂、粉剂或注射液的形式。
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