CN117503773A - 化合物kw-2449在制备抑制铁死亡药物中的应用 - Google Patents
化合物kw-2449在制备抑制铁死亡药物中的应用 Download PDFInfo
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Abstract
本发明公开了化合物KW‑2449在制备抑制铁死亡药物中的应用。通过体外抗铁死亡活性研究发现，化合物KW‑2449具有非常优异的抗铁死亡活性。经体内活性研究，化合物KW‑2449可抑制硫酸亚铁诱导的急性全身性铁过载诱发的多器官衰竭、阿霉素诱导的急性心肌损伤和缺血性脑损伤。因此，化合物KW‑2449在制备抑制铁死亡药物或者铁死亡相关疾病治疗药物方面具有非常好的应用前景。
Description
技术领域
本发明涉及铁死亡抑制剂，具体涉及化合物KW-2449在制备抑制铁死亡药物中的应用。属于医药技术领域。
背景技术
铁死亡是一种新型的程序性细胞死亡方式，其特征是铁依赖性脂质过氧化介导的膜损伤和随后细胞质膜破裂以及损伤相关分子模式的释放，并最终导致细胞死亡。发生铁死亡的细胞通常表现出坏死样的形态变化，包括细胞膜完整性丧失、细胞质肿胀、线粒体膜密度增加，嵴减少。由于细胞内容物的释放，发生铁死亡的细胞会引起体内大量炎症细胞浸润从而诱发严重的炎症反应。
铁死亡受到细胞内抗氧化系统和铁代谢的严格调控，目前已鉴定至少有四种信号通路参与细胞抗氧化和铁死亡调节：
1)SystemXc-GSH-GPX4系统；
2)FSP1–CoQ10；
3)GCH1-BH4-DHFR；
4)DHODH–ubiquinol。
目前的研究表明，铁死亡作为新的一类细胞程序性死亡方式，在恶性肿瘤、缺血性脑损伤、药源性心肌损伤等多种疾病的病理生理过程中起重要作用。
KW-2449是多靶点激酶抑制剂，其中文名为：[4-[2-(1H-吲唑-3-基)乙烯基]苯基]-1-哌嗪基甲酮，化学式为：C20H20N40。已有研究表明KW-2449可通过抑制FLT3缓解慢性粒细胞白血病、骨髓异常增生，亦可通过下调Bcr-Abl和AuroraA激酶活性改善白血病患者对伊马替尼耐药。最新研究发现，KW-2449可作为RIPK1激酶的抑制剂而发挥抗坏死性细胞凋亡的活性，并改善TNF-α诱导的全身性炎症反应综合征、对乙酰氨基酚诱导的急性肝损伤、顺铂诱导的急性肾损伤和抑制乳腺癌肿瘤肺转移等疾病。目前未有研究表明KW-2449可抑制铁死亡及缓解铁死亡相关性疾病。因此，发现KW-2449作为铁死亡抑制剂，并用于预防和/或治疗铁死亡相关疾病具有十分重要的意义。
发明内容
本发明的目的是为克服上述现有技术的不足，提供化合物KW-2449在制备抑制铁死亡药物中的应用。
为实现上述目的，本发明采用下述技术方案：
1、化合物KW-2449或其药学上可接受的盐在制备ULK1(unc-51like autophagyactivating kinase 1)激酶抑制剂中的应用。
化合物KW-2449的名称为[4-[2-(1H-吲唑-3-基)乙烯基]苯基]-1-哌嗪基甲酮，化学式为：C20H20N40，结构式如式(Ⅰ)所示：
2、化合物KW-2449或其药学上可接受的盐在制备抑制铁死亡药物中的应用。
优选的，KW-2449或其药学上可接受的盐通过抑制ULK1激酶活性从而抑制铁死亡。
优选的，所述药学上可接受的盐为有机酸盐或无机酸盐。
进一步优选的，所述有机酸包括但不限于：乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、对甲苯磺酸、水杨酸、草酸。
进一步优选的，所述无机酸包括但不限于：盐酸、硫酸、磷酸、二磷酸、氢溴酸、硝酸。
3、化合物KW-2449或其药学上可接受的盐在制备ULK1激酶抑制剂或铁死亡相关疾病治疗药物中的应用。
优选的，铁死亡相关疾病包括但不限于：硫酸亚铁诱导的急性全身性铁过载诱发的多器官衰竭、阿霉素诱导的急性心肌损伤和缺血性脑损伤。
4、组合物，包含前述的化合物KW-2449或其药学上可接受的盐。
5、前述组合物在制备ULK1激酶抑制剂或抑制铁死亡药物中的应用。
6、前述组合物在制备ULK1激酶抑制剂或铁死亡相关疾病治疗药物中的应用。
7、一种ULK1激酶抑制剂或抑制铁死亡药物，其有效成分为前述的化合物KW-2449或其药学上可接受的盐。
8、一种ULK1激酶抑制剂或铁死亡相关疾病治疗药物，其有效成分为前述的化合物KW-2449或其药学上可接受的盐。
9、一种ULK1激酶抑制剂或抑制铁死亡药物，包含前述组合物。
10、一种ULK1激酶抑制剂或铁死亡相关疾病治疗药物，包含前述组合物。
本发明的有益效果：申请人通过体外抗铁死亡活性研究发现，化合物KW-2449具有非常优异的抗铁死亡活性。经体内活性研究，化合物KW-2449可抑制硫酸亚铁(FeSO4·7H2O)诱导的急性全身性铁过载诱发的多器官衰竭、阿霉素诱导的急性心肌损伤和缺血性脑损伤。因此，化合物KW-2449在制备抑制铁死亡药物或者铁死亡相关疾病治疗药物方面具有非常好的应用前景。
附图说明
图1为KW-2449抑制RSL-3诱导的铁死亡。A为RSL-3诱导MEF细胞铁死亡，B为PI染色统计结果，C为KW-2449保护MEF细胞铁死亡的半数有效剂量为169.1nM，D为细胞脂质过氧化Liperfluo染色，E为细胞内MDA含量，F为细胞内抗氧化系统GSH/GSSG稳态。所有数值均为平均值±标准差形式(n＝3)。*：RSL-3组与给药组比较具有统计学差异(***：p<0.001)。
图2为KW-2449对不同细胞系及不同类型铁死亡抑制活性；其中，A为KW-2449抑制RSL-3诱导HK2细胞铁死亡，B为KW-2449抑制RSL-3诱导HT1080细胞铁死亡，C为KW-2449抑制RSL-3诱导H1299细胞铁死亡，D为KW-2449抑制Erastin诱导MEF细胞铁死亡，E为KW-2449抑制Erastin诱导HT1080细胞铁死亡，F为KW-2449抑制Erastin诱导HepG2细胞铁死亡，G为KW-2449抑制Cystine剥夺诱导MEF细胞铁死亡，H为KW-2449抑制RSL-3联合iFSP1诱导MEF细胞铁死亡，I为KW-2449抑制RSL-3联合iFSP1诱导MEF细胞铁死亡。所有数值均为平均值±标准差形式(n＝3)。*：RSL-3组与给药组比较具有统计学差异(***：p<0.001)。
图3为KW-2449抑制铁死亡不依赖于其对RIPK1激酶的抑制活性；其中，A为KW-2449可抑制Cisplatin诱导的MEF RIPK1-/-细胞死亡，B为PI染色统计结果，C为KW-2449保护Cisplatin诱导MEF RIPK1-/-细胞死亡的半数有效剂量为186.7nM。所有数值均为平均值±标准差形式(n＝3)。*：Cisplatin组与给药组比较具有统计学差异(***：p<0.001)。
图4为KW-2449不依赖于目前已报道的激酶抑制活性抑制铁死亡；其中，A为FLT3抑制剂FLT3 IN III在MEF细胞中的细胞毒性，B为极光激酶A和B抑制剂PF-03814735在MEF细胞中的细胞毒性，C为Bcr-Abl抑制剂GNF-7在MEF细胞中的细胞毒性，D为JAK2抑制剂Fedratinib在MEF细胞中的细胞毒性，E为Src抑制剂Saracatinib在MEF细胞中的细胞毒性，F为上述抑制剂在RSL-3诱导的MEF细胞铁死亡中的保护作用。所有数值均为平均值±标准差形式(n＝3)。*：RSL-3组与给药组比较具有统计学差异(***：p<0.001)；ns：RSL-3组与给药组比较不具有统计学差异。
图5为KW-2449可降低RSL-3诱导的胞内ROS水平；其中，A为KW-2449降低RSL-3诱导的MEF细胞内ROS，B为ROS平均荧光强度统计，C为KW-2449对RSL-3诱导的线粒体ROS没有影响，D为线粒体ROS平均荧光强度统计。所有数值均为平均值±标准差形式(n＝3)。*：RSL-3组与给药组比较具有统计学差异(***：p<0.001)；ns：RSL-3组与给药组比较不具有统计学差异。
图6为通过1，1-二苯基-2-三硝基苯肼(DPPH)实验证明KW-2449不是自由基清除剂。
图7为KW-2449通过阻断细胞自噬抑制RSL-3诱导的铁死亡；其中，A为在MEF细胞中KW-2449抑制RSL-3诱导的自噬相关蛋白活化，B为在HT-29细胞中KW-2449抑制RSL-3诱导的自噬相关蛋白活化，C为BafilomycinA1阻断细胞自噬流后KW-2449抑制RSL-3诱导的细胞自噬，D为KW-2449阻断RSL-3诱导的LC-3寡聚化。
图8为KW-2449抑制ULK1激酶酶活；其中，A为KW-2449抑制ULK1激酶酶活，B为KW-2449抑制ULK1激酶酶活的IC50为17.68nM。所有数值均为平均值±标准差形式(n＝3)。*：DMSO组与给药组比较具有统计学差异(***：p<0.001)。
图9为KW-2449缓解硫酸亚铁诱导的急性铁过载；其中，A为KW-2449降低急性铁过载小鼠死亡率，B为KW-2994降低小鼠血清AST水平，C为KW-2994降低小鼠血清ALT水平，D为KW-2994降低小鼠肝脏中MDA水平，E为KW-2449降低小鼠肝脏组织脂质过氧化，F为脂质过氧化产物4-HNE免疫组化定量分析，G为KW-2449降低急性铁过载小鼠肝脏细胞自噬水平。所有数值均为平均值±标准差形式(n＝3)。*：FeSO4.7H2O组与给药组比较具有统计学差异(***：p<0.001)。
图10为铁死亡抑制剂KW-2449缓解小鼠缺血性脑损伤；其中，A为脑缺血小鼠脑组织TTC染色结果，B为脑缺血小鼠神经功能障碍评分，C为脑缺血小鼠脑组织梗死体积。所有数值均为平均值±标准差形式(n＝3)。*：MCAO组与给药组比较具有统计学差异(*：p<0.05；**：p<0.01)。
图11为铁死亡抑制剂KW-2449缓解阿霉素诱导的心肌损伤；其中，A为KW-2449降低阿霉素诱导的小鼠死亡率，B为KW-2449缓解阿霉素诱导的心肌萎缩，C为KW-2449降低小鼠心肌组织脂质过氧化，D为脂质过氧化产物4-HNE免疫组化定量分析。所有数值均为平均值±标准差形式(n＝3)。*：DOX组与给药组比较具有统计学差异(*：p<0.05；***：p<0.001)。
具体实施方式
下面结合附图和实施例对本发明进行进一步的阐述，应该说明的是，下述说明仅是为了解释本发明，并不对其内容进行限定。
实施例1：KW-2449抑制RSL-3诱导的铁死亡
将KW-2449(MedChemExpress；Cat.HY-10339)用DMSO溶解成1mM母液备用，MEF细胞(ATCC:Cat.Bio-68384)铺12孔板，待细胞铺满底面80％时，按照预设组别分别加入KW-2449(1μM)或对应体积的DMSO，RSL-3(MedChemExpress；Cat.HY-100218A)用DMSO溶解成5mM母液，用5μM RSL-3刺激后8小时，在显微镜下观察KW-2449对RSL-3刺激后MEF细胞的保护作用，如图1中A所示，在1μM KW-2449的作用下，MEF细胞的存活率为85.77％。采用流式细胞术检测碘化吡啶(PI)染色后的活细胞数量，如图1中B所示，KW-2449显著保护细胞发生铁死亡。进一步采用流式细胞术方法考察了KW-24492的EC50为169.1nM(图1中C)。采用Liperfluo针对性染色细胞脂质过氧化水平，并采用流式细胞术检测发现KW-2449可显著缓解脂质过氧化水平(图1中D)，同时KW-2449可显著降低细胞内脂质过氧化产物丙二醛(MDA)的水平(图1中E)，并维持细胞内抗氧化系统稳态(图1中F)。
实施例2：KW-2449对不同细胞的铁死亡的抑制活性
使用人源的细胞系(HT1080；购置美国菌种保藏中心ATCC:Cat.Bio-68304,H1299；
ATCC:Cat.Bio-73106,HepG2；ATCC:Cat.Bio-53671,HK2；ATCC:Cat.Bio-74691)和鼠源的MEF细胞系，考察KW-2449对不同细胞系及不同铁死亡诱导剂刺激后抑制铁死亡的活性。结果如图2显示，KW-2449(1μM)能显著保护人源和鼠源细胞发生铁死亡。
实施例3：KW-2449不依赖于RIPK1抑制铁死亡
前期研究发现KW-2449可作为RIPK1激酶的抑制剂发挥抗坏死性凋亡的活性，为进一步考察KW-2449发挥抑制铁死亡的活性是否依赖于其对坏死性凋亡的调节，在MEF细胞中敲除RIPK1以阻断坏死性细胞凋亡。结果如图3中A和B所示，在1μM KW-2449的作用下，MEFRIPK1-/-细胞的存活率为84.30％，提示KW-2449可保护细胞发生铁死亡。进一步采用流式细胞术方法考察了KW-24492的EC50为186.7nM(图3中C)。
实施例4：KW-2449不依赖于目前已报道的激酶抑制活性抑制铁死亡
已有研究表明KW-2449是多靶点激酶抑制剂，对FLT3、ABL、ABLT315I、Aurorakinase、JAK2和c-Src激酶具有显著的抑制作用，其主要用于缓解慢性粒细胞白血病、骨髓异常增生、改善白血病患者对伊马替尼耐药性。为了验证KW-2449是否通过靶向抑制已知激酶活性缓解铁死亡，分别探究上述不同激酶特异性抑制剂对RSL-3诱导的铁死亡的缓解作用，结果发现现有激酶的抑制剂并不能缓解RSL-3诱导的铁死亡，该结果提示KW-2449并不是通过抑制已知激酶活性而发挥抗铁死亡的作用(图4中A-F)。
实施例5：KW-2449可通过抑制胞内ROS发挥抗铁死亡活性
MEF细胞在KW-2449(1μM)预处理30min后，用RSL-3(5μM)刺激4h，采用H2DCFDA探针检测细胞内ROS的水平，结果发现KW-2449可显著降低细胞内的ROS水平(图5中A、B)。采用MitoSOX Red探针检测细胞线粒体ROS水平，结果发现线粒体ROS并未发生明显的变化(图5中C、D)。
实施例6：KW-2449不是自由基清除剂
细胞内自由基参与脂质发生过氧化并促进细胞发生铁死亡，申请人在体外采用DPPH测定了KW-2449对自由基的清除作用。结果如图6所示，KW-2449并不能有效的去除自由基。
实施例7：KW-2449阻断细胞自噬抑制RSL-3诱导的铁死亡
已有研究表明细胞自噬在铁死亡中发挥重要的作用，在RSL-3诱导的MEF铁死亡中可明显的观察到细胞自噬，主要表现为ATG14磷酸化和LC-3II增强，而KW-2449可显著抑制RSL-3诱导的细胞自噬(图7中A)。同样的，可在HE-29细胞中观察到RSL-3诱导的细胞自噬和KW-2449阻断细胞自噬的效应(图7中B)。而采用BafilomycinA1阻断细胞自噬流并不影响KW-2449阻断RSL-3诱导的细胞自噬(图7中C)。RSL-3刺激可显著的促进GFP聚合，而KW-2449对LC-3的聚集具有极显著的阻断作用(图7中D)。
实施例8：KW-2449抑制ULK1激酶活性
已有研究发现ATG14可被ULK1激酶磷酸化并促进细胞自噬发生，KW-2449可显著抑制ULK1激酶活性(图8中A)。同时KW-2449抑制ULK1激酶活性的IC50为17.68nM(图8中B)。
实施例9：KW-2449缓解小鼠急性铁过载诱发的多器官衰竭
已有研究表明，硫酸亚铁腹腔注射可引起小鼠肝细胞发生铁死亡，为了探索KW-2449是否能够在体内保护硫酸亚铁诱导的小鼠急性铁过载，申请人在C57BL/6小鼠(南京模式动物所)中采用FeSO4·7H2O诱导了小鼠急性铁过载模型。将KW-2449溶解于质量浓度0.5％甲基纤维素钠溶液中，配置成1mg/ml的悬浊液，按小鼠体重(10ml/kg)分别灌胃相应剂量的KW-2449或溶剂，每12h灌胃一次，总计灌胃2次。末次灌胃KW-2449半小时后腹腔注射FeSO4·7H2O(500ml/kg)。每隔4h记录小鼠存活水平，72h后处理小鼠，取其肝脏检测KW-2449的保护作用。结果发现FeSO4·7H2O可显著降低小鼠存活(图9中A)和加剧小鼠肝脏损伤，主要表现为血清中ALT和AST水平的增加，而KW-2449可显著缓解肝损伤(图9中B、C)。同时KW-2449可显著改善肝细胞脂质过氧化，缓解FeSO4·7H2O诱导肝细胞发生铁死亡(图9中D-F)。急性铁过载可明显促进肝脏组织细胞自噬，主要表现为ATG14磷酸化和IL-3II增强，而KW-2449同样可抑制铁过载诱导的肝脏细胞自噬(图9中G)。
小鼠急性铁过载模型的构建参考以下文献：Van Coillie,S.；Van San,E.；Goetschalckx,I.；Wiernicki,B.；Mukhopadhyay,B.；Tonnus,W.；Choi,S.M.；Roelandt,R.；Dumitrascu,C.；Lamberts,L.；Dams,G.；Weyts,W.；Huysentruyt,J.；Hassannia,B.；Ingold,I.；Lele,S.；Meyer,E.；Berg,M.；Seurinck,R.；Saeys,Y.；Vermeulen,A.；vanNuijs,A.L.N.；Conrad,M.；Linkermann,A.；Rajapurkar,M.；Vandenabeele,P.；Hoste,E.；Augustyns,K.；Vanden Berghe,T.,Targeting ferroptosis protects againstexperimental(multi)organ dysfunction and death.Nat Commun 2022,13(1),1046.
实施例10：铁死亡抑制剂KW-2449缓解小鼠缺血性脑损伤
缺血性脑卒中会引起能量消耗、线粒体损伤、ROS生成和炎症因子的释放，铁死亡相关基因和蛋白表达异常，脑内ROS和脂质过氧化物水平升高，而GPX4和还原性谷胱甘肽呈现耗竭状态。在小鼠缺血/再灌注损伤模型中，KW-2449可显著改善小鼠脑组织血液供给(图10中A)，降低小鼠神经损伤及脑组织梗死面积(图10中B、C)。
实施例11：铁死亡抑制剂KW-2449缓解阿霉素诱导的心肌损伤
铁死亡在阿霉素(Doxorubicin)诱导的心肌损伤和心肌细胞死亡中发挥着重要的作用，抑制铁死亡可显著逆转DOX诱导的心脏毒性。在DOX诱导的心肌损伤模型中，KW-2449可显著改善小鼠存活水平(图11中A)，改善小鼠心脏萎缩损伤(图11中B)，在DOX诱导的小鼠心脏中可4-HNE染色阳性，提示在小鼠心脏中存在明显的脂质过氧化和细胞铁死亡(图11中C、D)，KW-2449可显著改善小鼠心脏组织脂质过氧化和细胞铁死亡(图11中C、D)。
心肌损伤模型的构建参考以下文献：Wu,X.；Wang,L.；Wang,K.；Li,J.；Chen,R.；Wu,X.；Ni,G.；Liu,C.；Das,S.；Sluijter,J.P.G.；Li,X.；Xiao,J.,ADAR2 increases inexercised heart andprotects against myocardial infarction and doxorubicin-induced cardiotoxicity.Mol Ther 2022,30(1),400-414.
以上实验结果表明，本发明的化合物KW-2449具有优异的抗铁死亡活性，可作为铁死亡抑制剂，可抵抗缺血性脑损伤、硫酸亚铁诱导的多器官衰竭和阿霉素诱导的急性心肌损伤，可用于制备铁死亡抑制剂及铁死亡相关疾病的药物。
综上，因此本发明化合物及其盐类可以用于制备铁死亡抑制剂。
上述虽然结合附图对本发明的具体实施方式进行了描述，但并非对本发明保护范围的限制，在本发明的技术方案的基础上，本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。
Claims (10)
1.化合物KW-2449或其药学上可接受的盐在制备ULK1激酶抑制剂中的应用。
2.化合物KW-2449或其药学上可接受的盐在制备抑制铁死亡药物中的应用。
3.化合物KW-2449或其药学上可接受的盐在制备ULK1激酶抑制剂或铁死亡相关疾病治疗药物中的应用。
4.组合物，包含前述的化合物KW-2449或其药学上可接受的盐。
5.权利要求4所述组合物在制备ULK1激酶抑制剂或抑制铁死亡药物中的应用。
6.权利要求4所述组合物在制备ULK1激酶抑制剂或铁死亡相关疾病治疗药物中的应用。
7.一种ULK1激酶抑制剂或抑制铁死亡药物，其特征在于，有效成分为化合物KW-2449或其药学上可接受的盐。
8.一种ULK1激酶抑制剂或铁死亡相关疾病治疗药物，其特征在于，其有效成分为前述的化合物KW-2449或其药学上可接受的盐。
9.一种ULK1激酶抑制剂或抑制铁死亡药物，其特征在于，包含权利要求3所述组合物。
10.一种ULK1激酶抑制剂或铁死亡相关疾病治疗药物，其特征在于，包含权利要求3所述组合物。
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