CN115381956B - 一种治疗癌症的药物组合物及其用途 - Google Patents
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Abstract
本发明提供了一种治疗癌症的药物组合物及其用途,属于医药领域。该药物组合物是由FAK抑制剂和CD44抑制剂组成。本发明还提供了FAK抑制剂和CD44抑制剂联合用药治疗癌症。本发明CD44抑制剂和FAK抑制剂联合用药,能够发挥协同增效的作用,显著提高对肿瘤的抑制效果,降低毒副作用,并克服肿瘤耐药性,为临床治疗癌症提供了良好的选择。
Description
技术领域
本发明属于医药领域,具体涉及一种治疗癌症的药物组合物及其用途。
背景技术
癌症通常泛指所有恶性肿瘤,具有细胞分化和增殖异常、生长失去控制、浸润性和转移性等生物学特征。每年因为各种癌症死亡人数很多,严重威胁人类的生存。目前肿瘤的临床治疗依然以手术、化疗药物为主,但进入二十一世纪以来分子靶向药物治疗正扮演着越来越重要的角色。分子靶向药物相较于传统的细胞毒性药物,因为以肿瘤细胞不同于正常细胞的特征为靶点,由盲目攻击变为有的放矢,在发挥强大的抗肿瘤作用同时,减少了对正常器官和组织的毒副作用,从而改善患者生存质量,因此成为肿瘤治疗药物研发的热点。
CD44是一种细胞表面跨膜糖蛋白,主要参与异质性粘附,即肿瘤细胞与宿主细胞和宿主基质的粘附,异质性粘附在肿瘤细胞侵袭转移中起促进作用。文献《Anti-CD44antibodies inhibitboth mTORC1 and mTORC2:a new rationale supporting CD44-induced AML differentiation therapy》(Merzaban,J,S,et al.Leukemia:Officialjournal of the Leukemia Society of America,Leukemia Research Fund,U.K,2016.)发现用抗体抑制CD44,可导致两个参与癌细胞异常生长的主要通路的表达下降:PI3K(磷脂酰肌醇3激酶)通路和mTOR(哺乳动物雷帕霉素靶蛋白)通路。因此CD44抑制剂有望应用于治疗癌症。虽然CD44抑制剂表现出良好的抗癌活性,但在临床试验中发现其具有较高的毒副作用(《CD44V6-targeted imaging of head and neck squamous cell carcinoma:antivody-based approaches》,《Hyaluronic acid targeting ofCD44 forcancertherapy:from receptorbiologyto nanomedicine》)。
局部黏着斑激酶(focal adhesion kinase,FAK)是一种非受体型酪氨酸蛋白激酶,是细胞内重要的骨架蛋白与多种信号通路的关键分子。FAK在肿瘤发生、发展、迁移和侵袭的各个阶段都具有重要作用。目前,FAK被当作潜在的肿瘤治疗靶点,FAK抑制剂作为配体,可与ATP竞争性结合FAK受体的结合位点,阻断FAK介导的生长、增殖信号通路的信息传递,导致恶性肿瘤细胞生长增殖受抑制,甚至在大剂量时导致细胞死亡。但是FAK抑制剂同样存在毒副作用大的问题。而且,随着研究深入,还发现FAK在癌症病情发展中所起的生物学作用是复杂的,其治疗癌症效果并不能确定。
并且,在治疗癌症过程中,耐药性问题一直是一个很大的困扰。如何克服癌细胞耐药性,也是癌症治疗研究的一个难点。目前尚未见将CD44抑制剂和FAK抑制剂联合使用制备治疗癌症的药物,其是否具有治疗癌症的效果,毒副作用是否降低,是否可以克服癌细胞耐药性都有待进一步研究。
发明内容
本发明的目的是提供一种治疗癌症的药物组合物及其用途。
本发明提供了一种治疗癌症的药物组合物,它是由FAK抑制剂和CD44抑制剂组成。
进一步地,所述FAK抑制剂和CD44抑制剂的重量比为1:10~10:1。
进一步地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018、APG-2449;
或者,所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
其中,R1、R2分别独立选自氢、甲基、三氘代甲基;
或者,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
优选地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Defactinib或IN10018。
进一步地,所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物、或多肽、或抗体:Angstrom6、PEP-1、AMC303、Anti-CD44 mAb H4C4、anti-CD44 mAb HI44a、anti-CD44 mAb IM7、anti-CD44 mAb KM201、RO5429083、RG7356、anti-CD44V6 mAb 2F10、anti-CD44V6 mAb U36、anti-CD44V6 mAbV6B3、anti-CD44V6 mAb VFF18、anti-CD44V6 mAb VFF4、anti-CD44V6 mAb VFF7;
优选地,所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:AMC303。
进一步地,所述FAK抑制剂和CD44抑制剂的摩尔比为1:82~82:1;
优选地,所述FAK抑制剂和CD44抑制剂的摩尔比为0.4~81:1。
进一步地,所述FAK抑制剂为化合物或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和CD44抑制剂的摩尔比为0.4~81:1;
或者,所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和CD44抑制剂的摩尔比为0.4~27:1;
或者,所述FAK抑制剂为IN10018、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和CD44抑制剂的摩尔比为1:1。
本发明还提供了一种前述的药物组合物的制备方法,它包括如下步骤:按照重量比取FAK抑制剂和CD44抑制剂,混合,即可。
本发明还提供了前述的药物组合物在制备治疗癌症的药物中的用途;
优选地,所述癌症为实体瘤、间皮瘤、黑素瘤、前列腺癌、乳腺癌、胶质母细胞瘤、脑癌;
所述实体瘤包括间皮瘤、胰腺癌、软组织肿瘤、转移瘤、非固体癌、肉瘤、腺癌、肺癌、乳腺癌、淋巴瘤、胃肠道癌、泌尿生殖系统癌、前列腺癌、卵巢癌;所述胃肠道癌包括结肠癌、所述泌尿生殖系统癌包括肾、尿路上皮或睾丸肿瘤;所述卵巢癌包括晚期卵巢癌;
所述间皮瘤包括神经纤维瘤、肾癌、肺癌、小细胞肺癌、非小细胞肺癌、KRAS突变体非小细胞肺癌、肝癌、甲状腺癌、乳腺癌、神经系统肿瘤、神经鞘瘤、脑膜瘤、神经瘤、腺样囊性癌、室管膜瘤、室管膜肿瘤、恶性胸膜瘤、恶性胸膜间皮瘤、三联体瘤、阴性乳腺癌、非血液恶性肿瘤、黑素瘤、结直肠癌、白血病、腺癌、固体肿瘤;
所述黑素瘤包括局部晚期黑素瘤、局部突变的N-Ras引起的黑素瘤、转移性恶性皮肤黑色素瘤;所述结直肠癌包括转移性结直肠癌;所述白血病包括急性髓性白血病;所述腺癌包括腺癌;所述固体肿瘤包括局部晚期实体瘤、转移性实体瘤、肝细胞癌;
所述前列腺癌包括去势抵抗性前列腺癌、转移性去势抵抗性前列腺癌;
所述脑癌包括神经上皮组织肿瘤、脑胶质瘤、星形细胞瘤、少突胶质瘤、室管膜与脉络丛肿瘤、松果体肿瘤、神经细胞肿瘤、神经节细胞瘤、神经母细胞瘤、分化不良的肿瘤、胚胎性肿瘤、多形胶质母细胞瘤、髓母细胞瘤、神经鞘膜瘤、脑膜瘤、恶性淋巴癌、脑血管肿瘤、畸形性胛溜、腕咽賫瘤,血管畸形毛细血管扩张、垂体肿瘤、转移性肿瘤。
本发明还提供了一种治疗癌症的药物制剂,它是由前述的药物组合物为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
本发明还提供了一种治疗癌症的联合用药物,它含有相同或者不同规格的同时或者分别给药的FAK抑制剂和CD44抑制剂,以及药学上可接受的载体;
优选地,所述FAK抑制剂和CD44抑制剂的重量比为1:10~10:1;
或者,所述FAK抑制剂和CD44抑制剂的摩尔比为1:82~82:1;
更优选地,所述FAK抑制剂和CD44抑制剂的摩尔比为0.4~81:1。
进一步地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018、APG-2449;
或者,所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
其中,R1、R2分别独立选自氢、甲基、三氘代甲基;
或者,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
优选地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
Defactinib或IN10018。
进一步地,所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物、或多肽、或抗体:Angstrom6、PEP-1、AMC303、Anti-CD44 mAb H4C4、anti-CD44 mAb HI44a、anti-CD44 mAb IM7、anti-CD44 mAb KM201、RO5429083、RG7356、anti-CD44V6 mAb 2F10、anti-CD44V6 mAb U36、anti-CD44V6 mAbV6B3、anti-CD44V6 mAb VFF18、anti-CD44V6 mAb VFF4、anti-CD44V6 mAb VFF7;
优选地,所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:AMC303。
进一步地,所述FAK抑制剂为化合物或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和CD44抑制剂的摩尔比为0.4~81:1;
或者,所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和CD44抑制剂的摩尔比为0.4~27:1;
或者,所述FAK抑制剂为IN10018、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和CD44抑制剂的摩尔比为1:1。
本发明还提供了FAK抑制剂和CD44抑制剂联用在制备治疗癌症的药物中的用途;
优选地,所述FAK抑制剂和CD44抑制剂的重量比为1:10~10:1。
或,所述FAK抑制剂和CD44抑制剂的摩尔比为1:82~82:1;
更优选地,所述FAK抑制剂和CD44抑制剂的摩尔比为0.4~81:1。
进一步地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018、APG-2449;
或者,所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
其中,R1、R2分别独立选自氢、甲基、三氘代甲基;
或者,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
优选地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
Defactinib或IN10018。
进一步地,所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物或多肽或抗体:Angstrom6、PEP-1、AMC303、Anti-CD44 mAb H4C4、anti-CD44 mAb HI44a、anti-CD44 mAb IM7、anti-CD44 mAb KM201、RO5429083、RG7356、anti-CD44V6 mAb 2F10、anti-CD44V6 mAb U36、anti-CD44V6 mAbV6B3、anti-CD44V6 mAb VFF18、anti-CD44V6 mAb VFF4、anti-CD44V6 mAb VFF7;
优选地,所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:AMC303。
进一步地,所述FAK抑制剂为化合物或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和CD44抑制剂的摩尔比为0.4~81:1;
或者,所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和CD44抑制剂的摩尔比为0.4~27:1;
或者,所述FAK抑制剂为IN10018、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和CD44抑制剂的摩尔比为1:1。
进一步地,所述癌症为实体瘤、间皮瘤、黑素瘤、前列腺癌、乳腺癌、胶质母细胞瘤、脑癌;
所述实体瘤包括间皮瘤、胰腺癌、软组织肿瘤、转移瘤、非固体癌、肉瘤、腺癌、肺癌、乳腺癌、淋巴瘤、胃肠道癌、泌尿生殖系统癌、前列腺癌、卵巢癌;所述胃肠道癌包括结肠癌、所述泌尿生殖系统癌包括肾、尿路上皮或睾丸肿瘤;所述卵巢癌包括晚期卵巢癌;
所述间皮瘤包括神经纤维瘤、肾癌、肺癌、小细胞肺癌、非小细胞肺癌、KRAS突变体非小细胞肺癌、肝癌、甲状腺癌、乳腺癌、神经系统肿瘤、神经鞘瘤、脑膜瘤、神经瘤、腺样囊性癌、室管膜瘤、室管膜肿瘤、恶性胸膜瘤、恶性胸膜间皮瘤、三联体瘤、阴性乳腺癌、非血液恶性肿瘤、黑素瘤、结直肠癌、白血病、腺癌、固体肿瘤;
所述黑素瘤包括局部晚期黑素瘤、局部突变的N-Ras引起的黑素瘤、转移性恶性皮肤黑色素瘤;所述结直肠癌包括转移性结直肠癌;所述白血病包括急性髓性白血病;所述腺癌包括腺癌;所述固体肿瘤包括局部晚期实体瘤、转移性实体瘤、肝细胞癌;
所述前列腺癌包括去势抵抗性前列腺癌、转移性去势抵抗性前列腺癌;
所述脑癌包括神经上皮组织肿瘤、脑胶质瘤、星形细胞瘤、少突胶质瘤、室管膜与脉络丛肿瘤、松果体肿瘤、神经细胞肿瘤、神经节细胞瘤、神经母细胞瘤、分化不良的肿瘤、胚胎性肿瘤、多形胶质母细胞瘤、髓母细胞瘤、神经鞘膜瘤、脑膜瘤、恶性淋巴癌、脑血管肿瘤、畸形性胛溜、腕咽賫瘤,血管畸形毛细血管扩张、垂体肿瘤、转移性肿瘤。
本发明CD44抑制剂和FAK抑制剂联合用药,能够发挥协同增效的作用,显著提高对肿瘤的抑制效果,降低毒副作用,并克服肿瘤耐药性,为临床治疗癌症提供了良好的选择。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为化合物25和AMC303在A549细胞中联用生存率柱状图。
图2为Defactinib和AMC303在A549细胞中联用生存率柱状图。
图3为化合物25、Defactinib或IN10018和AMC303在A549细胞中联用划痕实验图。
图4为化合物25、Defactinib或IN10018和AMC303在A549细胞中联用划痕实验统计图。
图5为化合物25和AMC303在SW620细胞中联用生存率柱状图。
图6为Defactinib和AMC303在SW620细胞中联用生存率柱状图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
本发明实施例中,化合物25结构为按照申请号为201910373081.2的专利所述方法制备。Defactinib为市售FAK抑制剂。AMC303是amcureGmbH公司开发的CD44v6抑制剂,购买获得。IN10018是一种FAK抑制剂,购买获得。
实施例1、本发明药物组合物抑制癌症细胞增殖的效果
1、实验方法
取处于对数生长期的非小细胞肺癌A549细胞,以1.0×103个/孔的浓度接种于96孔培养板中。并于37℃,5%的CO2浓度及饱和湿度条件的培养箱中孵育24小时。孵育24小时后,将药物FAK抑制剂(化合物25或Defactinib)和CD44抑制剂(AMC303)先后加入96孔板。阴性对照孔加入和药物同体积的含10%胎牛血清的RPMI 1640细胞培养液。
化合物25的浓度为:0μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
Defactinib的浓度为:0μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
AMC303的浓度为:0μM、0.002μM、0.005μM、0.014μM、0.041μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
加入药物共孵育6天后,每孔加入10μL CCK-8,继续培养2.5小时。于酶标仪中按照波长450nm进行各孔吸光度值(OD)测定。按公式计算细胞生长抑制率。抑制率(%)=(1-加药孔OD值/对照孔OD值)×100%。再按照q=Ea+b/(Ea+Eb-Ea*Eb)药物联合指数进行判定。q值判定标准如表1所示:
表1.q值判定标准
2、实验结果
(1)化合物25和AMC303联合用药(化合物25&AMC303)
化合物25和AMC303联合用药结果如图1所示。由图1可知:当化合物25和AMC303的摩尔比为81:1时,化合物25和AMC303联合用药对于抑制A549细胞生长有协同增效作用,可用于协同增效治疗非小细胞肺癌。
(2)Defactinib和AMC303联合用药(Defactinib&AMC303)
Defactinib和AMC303联合用药结果如图2所示。由图2可知:当Defactinib和AMC303的摩尔比为27:1时,Defactinib和AMC303联合用药对于抑制A549细胞生长有协同增效作用,可用于协同增效治疗非小细胞肺癌。
上述实施例提供了一种治疗非小细胞肺癌的联合用药物,实验结果说明FAK抑制剂(化合物25或Defactinib)与CD44抑制剂AMC303联合用药可以显著抑制非小细胞肺癌细胞的生长增殖,其抗癌效果明显优于FAK抑制剂(化合物25或Defactinib)和CD44抑制剂AMC303单独使用,具有协同增效作用。本发明的联合用药物在非小细胞肺癌的治疗领域具有很好的临床应用前景。
实施例2、本发明药物组合物抑制癌症细胞迁移的效果
1、实验方法
取处于对数生长期的非小细胞肺癌A549细胞,以1.0×106个/孔的浓度接种于12孔培养板中。并于37℃,5%的CO2浓度及饱和湿度条件的培养箱中孵育24小时。将12孔板中的细胞进行划痕,每孔3道划痕,划痕后吸弃培养基再用PBS漂洗一遍除去漂浮细胞。将FAK抑制剂(化合物25、Defactinib或IN10018)和CD44抑制剂(AMC303)先后加入12孔板。药物均使用含20ng/ml HGF的无血清RPMI 1640细胞培养液进行配制。阴性对照孔加入和药物同体积的无血清的RPMI 1640细胞培养液(含20ng/ml HGF)。
化合物25浓度为:0.4μM;
Defactinib浓度为:0.4μM;
IN10018浓度为:1μM;
AMC303浓度为:1μM。
单独加入4种药物(化合物25、Defactinib、IN10018、AMC303),或者同时加入化合物25和AMC303(化合物25&AMC303,化合物25浓度为0.4μM,AMC303浓度为1μM),或者同时加入Defactinib和AMC303(Defactinib&AMC303,Defactinib浓度为0.4μM,AMC303浓度为1μM),或者同时加入IN10018和AMC303(IN10018&AMC303,IN10018浓度为1μM,AMC303浓度为1μM),孵育24小时后,吸弃培养基,用PBS漂洗一遍除去漂浮细胞,于显微镜下观察细胞迁移情况,并使用放大倍数为目镜10×物镜10×进行拍照(0h及24h均需拍照)。使用Image J进行图片处理分析细胞迁移率。迁移率计算公式:
迁移率(%)=[划痕面积(0h)-划痕面积(48h)]/划痕面积(0h)×100%
使用迁移率通过Prism统计制作柱状图并进行t检验。若p<0.05即有显著差异。
2、实验结果
细胞迁移结果如图3-4和表2所示。
表2.各组细胞迁移结果显著性差异统计结果
药物组合 | P值 |
化合物25&AMC303vs化合物25 | 0.046 |
化合物25&AMC303vsAMC303 | 0.036 |
Defactinib&AMC303vsDefactinib | 0.028 |
Defactinib&AMC303vsAMC303 | 0.016 |
IN10018&AMC303vsIN10018 | 0.045 |
IN10018&AMC303vsAMC303 | 0.014 |
由图3-4以及表2可知:FAK抑制剂(化合物25、Defactinib或IN10018)与CD44抑制剂AMC303联合用药可以显著抑制非小细胞肺癌细胞的迁移,其抗癌效果明显优于FAK抑制剂(化合物25、Defactinib或IN10018)、CD44制剂AMC303单独使用,具有协同增效作用。本发明的联合用药物在非小细胞肺癌的治疗领域具有很好的临床应用前景。
实施例3、本发明药物组合物抑制癌症细胞增殖的效果
1、实验方法
取处于对数生长期的结直肠癌SW620细胞,以1.0×103个/孔的浓度接种于96孔培养板中。并于37℃,5%的CO2浓度及饱和湿度条件的培养箱中孵育24小时。孵育24小时后,将药物FAK抑制剂(化合物25或Defactinib)和CD44抑制剂(AMC303)先后加入96孔板。阴性对照孔加入和药物同体积的含10%胎牛血清的RPMI 1640细胞培养液。
化合物25的浓度为:0μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
Defactinib的浓度为:0μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
AMC303的浓度为:0μM、0.002μM、0.005μM、0.014μM、0.041μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
加入药物共孵育6天后,每孔加入10μL CCK-8,继续培养2.5小时。于酶标仪中按照波长450nm进行各孔吸光度值(OD)测定。按公式计算细胞生长抑制率。抑制率(%)=(1-加药孔OD值/对照孔OD值)×100%。再按照q=Ea+b/(Ea+Eb-Ea*Eb)药物联合指数进行判定。q值判定标准如表3所示:
表3.q值判定标准
2、实验结果
(1)化合物25和AMC303联合用药(化合物25&AMC303)
化合物25和AMC303联合用药结果如图5所示。由图5可知:当化合物25和AMC303的摩尔比为81:1时,化合物25和AMC303联合用药对于抑制SW620细胞生长有协同增效作用,可用于协同增效治疗结直肠癌。
(2)Defactinib和AMC303联合用药(Defactinib&AMC303)
Defactinib和AMC303联合用药结果如图6所示。由图6可知:当Defactinib和AMC303的摩尔比为1:1时,Defactinib和AMC303联合用药对于抑制SW620细胞生长有协同增效作用,可用于协同增效治疗结直肠癌。
上述实施例提供了一种治疗结直肠癌的联合用药物,实验结果说明FAK抑制剂(化合物25或Defactinib)与CD44抑制剂AMC303联合用药可以显著抑制结直肠癌细胞的生长增殖,其抗癌效果明显优于FAK抑制剂(化合物25或Defactinib)和CD44抑制剂AMC303单独使用,具有协同增效作用。本发明的联合用药物在结直肠癌的治疗领域具有很好的临床应用前景。
综上,本发明研究发现CD44抑制剂和FAK抑制剂联合用药,能够发挥协同增效的作用,显著提高对肿瘤的抑制效果,并克服肿瘤耐药性,为临床治疗癌症提供了良好的选择。
Claims (6)
1.一种治疗癌症的药物组合物,其特征在于:它是由FAK抑制剂和CD44抑制剂组成:
所述FAK抑制剂为化合物或其盐;所述CD44抑制剂为AMC303或其盐;所述FAK抑制剂和CD44抑制剂的摩尔比为81:1;
或者,所述FAK抑制剂为Defactinib或其盐;所述CD44抑制剂为AMC303或其盐;所述FAK抑制剂和CD44抑制剂的摩尔比为27:1或1:1。
2.一种权利要求1所述的药物组合物的制备方法,其特征在于:它包括如下步骤:按照重量比取FAK抑制剂和CD44抑制剂,混合,即可。
3.权利要求1所述的药物组合物在制备治疗癌症的药物中的用途;
所述癌症为肺癌、结直肠癌。
4.一种治疗癌症的药物制剂,其特征在于:它是由权利要求1所述的药物组合物为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
5.一种治疗癌症的联合用药物,其特征在于:它含有相同或者不同规格的同时或者分别给药的FAK抑制剂和CD44抑制剂,以及药学上可接受的载体;
所述FAK抑制剂为化合物或其盐;所述CD44抑制剂为AMC303或其盐;所述FAK抑制剂和CD44抑制剂的摩尔比为81:1;
或者,所述FAK抑制剂为Defactinib或其盐;所述CD44抑制剂为AMC303或其盐;所述FAK抑制剂和CD44抑制剂的摩尔比为27:1或1:1。
6.FAK抑制剂和CD44抑制剂联用在制备治疗癌症的药物中的用途;
所述FAK抑制剂为化合物或其盐;所述CD44抑制剂为AMC303或其盐;所述FAK抑制剂和CD44抑制剂的摩尔比为81:1;
或者,所述FAK抑制剂为Defactinib或其盐;所述CD44抑制剂为AMC303或其盐;所述FAK抑制剂和CD44抑制剂的摩尔比为27:1或1:1;
所述癌症为肺癌、结直肠癌。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2954933A1 (en) * | 2014-06-10 | 2015-12-16 | 3B Pharmaceuticals GmbH | Conjugate comprising a neurotensin receptor ligand |
CN106349158A (zh) * | 2016-08-03 | 2017-01-25 | 杭州市西溪医院 | 一种c‑Met小分子抑制剂、含其的药物组合物及其药学应用 |
CN111377871A (zh) * | 2018-12-27 | 2020-07-07 | 成都海创药业有限公司 | 一种fak抑制剂及其联合用药物 |
Family Cites Families (4)
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US8697629B2 (en) * | 2010-03-05 | 2014-04-15 | Angstrom Pharmaceuticals, Inc. | Modulation of intracellular signaling |
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MX2022004370A (es) * | 2019-10-18 | 2022-05-06 | Forty Seven Inc | Terapias de combinacion para tratar sindromes mielodisplasicos y leucemia mieloide aguda. |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2954933A1 (en) * | 2014-06-10 | 2015-12-16 | 3B Pharmaceuticals GmbH | Conjugate comprising a neurotensin receptor ligand |
CN106349158A (zh) * | 2016-08-03 | 2017-01-25 | 杭州市西溪医院 | 一种c‑Met小分子抑制剂、含其的药物组合物及其药学应用 |
CN111377871A (zh) * | 2018-12-27 | 2020-07-07 | 成都海创药业有限公司 | 一种fak抑制剂及其联合用药物 |
Non-Patent Citations (3)
Title |
---|
Administration of PLGA nanoparticles carrying shRNA against focal adhesion kinase and CD44 results in enhanced antitumor effects against ovarian cancer;L Zou,等;《Cancer Gene Therapy》;第20卷;摘要,第244-250页 * |
Colon Cancer Experimental Therapy AMC303 Also Inhibits Pancreatic Tumors in Mice;DANIELA SEMEDO;《https://coloncancernewstoday.com/2017/04/20/colon-cancer-therapy-amc303-inhibited-pancreatic-cancer-in-mouse-model/#:~:text=AMC303%20inhibited%20tumor%20growth%20and%20prevented%20the%20spread,Association%20for%20Cancer%20Research%E2%80%99s%20annual%20meeting%20in%20Washington》;正文第2-3页 * |
L Zou,等.Administration of PLGA nanoparticles carrying shRNA against focal adhesion kinase and CD44 results in enhanced antitumor effects against ovarian cancer.《Cancer Gene Therapy》.2013,第20卷摘要,第244-250页. * |
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WO2022247829A1 (zh) | 2022-12-01 |
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