CN113423429A - Nlrp3炎性体抑制 - Google Patents
Nlrp3炎性体抑制 Download PDFInfo
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- CN113423429A CN113423429A CN202080014066.XA CN202080014066A CN113423429A CN 113423429 A CN113423429 A CN 113423429A CN 202080014066 A CN202080014066 A CN 202080014066A CN 113423429 A CN113423429 A CN 113423429A
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Abstract
本发明涉及一种NLRP3炎性体的结合位点。本发明还涉及一种用于抑制NLRP3活化且治疗对NLRP3抑制有响应的疾病、病症或疾患的方法和化合物。本发明还涉及一种通过抑制NLRP3活化来减少细胞或线粒体活性氧物质(ROS)的方法。本发明还涉及一种筛选化合物以测定所述化合物与所述NLRP3炎性体的所述结合位点的结合程度的方法,并且涉及一种通过这种筛选方法鉴定的化合物。
Description
技术领域
本发明涉及一种NLRP3炎性体的结合位点。本发明还涉及一种用于抑制NLRP3活化且治疗对NLRP3抑制有响应的疾病、病症或疾患的方法和化合物。本发明还涉及一种通过抑制NLRP3活化来减少细胞或线粒体活性氧物质(Reactive Oxygen Specie;ROS)的方法。本发明还涉及一种筛选化合物以测定所述化合物与所述NLRP3炎性体的所述结合位点的结合程度的方法,并且涉及一种通过这种筛选方法鉴定的化合物。
发明背景
炎性体负责炎症反应的活化。NOD样受体(NLR)家族含热蛋白(pyrin)结构域的蛋白质3(NLRP3)炎性体为炎症过程的组分,且其异常活性在遗传性病症(例如隐热蛋白相关周期性综合征(cryopyrin-associated periodic syndrome;CAPS))和复杂疾病(例如,多发性硬化症、2型糖尿病、阿尔茨海默氏病(Alzheimer’s disease)和动脉粥样硬化症)中是致病性的。
NLRP3为感测许多病原体衍生、环境和宿主衍生的因素的胞内信号传导分子。在活化后,NLRP3与含有胱天蛋白酶活化和募集结构域(ASC)的细胞凋亡相关斑点样蛋白质结合。ASC随后聚合以形成称为ASC斑点的大凝集体。聚合的ASC继而与半胱氨酸蛋白酶胱天蛋白酶-1相互作用以形成称为炎性体的复合物。这引起胱天蛋白酶-1的活化,所述胱天蛋白酶-1裂解促炎性细胞因子IL-1β和IL-18(分别称为pro-IL-1β和pro-IL-18)的前体形式,以由此活化这些细胞因子。胱天蛋白酶-1还介导一种类型的炎症性细胞死亡,称为细胞焦亡。ASC斑点还可募集且活化胱天蛋白酶-8,所述胱天蛋白酶-8可处理pro-IL-1β和pro-IL-18且触发凋亡细胞死亡。
胱天蛋白酶-1将pro-IL-1β和pro-IL-18裂解为其从细胞分泌的活性形式。活性胱天蛋白酶-1还裂解消皮素D(gasdermin-D)以触发细胞焦亡。通过其对热解细胞死亡路径的控制,胱天蛋白酶-1还介导警报素(alarmin)分子(例如IL-33)和高迁移率族1蛋白质(HMGB1)的释放。胱天蛋白酶-1还裂解胞内IL-1R2,从而引起其降解且允许释放IL-1α。在人类细胞中,胱天蛋白酶-1还可控制IL-37的处理和分泌。多个其它胱天蛋白酶-1底物(例如细胞骨架和糖酵解路径的组分)可有助于胱天蛋白酶-1-依赖性炎症。
将NLRP3依赖性ASC斑点释放到胞外环境中,在所述胞外环境中其可活化胱天蛋白酶-1,诱导对胱天蛋白酶-1底物的处理且传播炎症。
来源于NLRP3炎性体活化的活性细胞因子为炎症的重要驱动子且与其它细胞因子途径相互作用以使对感染和损伤的免疫反应成形。举例来说,IL-1β信号传导诱导促炎性细胞因子IL-6和TNF的分泌。IL-1β和IL-18与IL-23协同诱导记忆CD4 Th17细胞和γδT细胞在不存在T细胞受体接合的情况下产生IL-17。IL-18和IL-12还协同诱导从记忆T细胞和NK细胞产生IFN-γ,从而驱动Th1反应。
遗传性CAPS疾病穆-韦二氏综合征(Muckle-Wells syndrome;MWS)、家族性冷因性自身炎症综合征(FCAS)和新生儿发作型多系统炎症性疾病(NOMID)由NLRP3中的功能获得突变引起,因此将NLRP3定义为炎症过程的关键组分。NLRP3还涉及多种复杂疾病的发病机制,所述疾病尤其包括代谢障碍,例如2型糖尿病、动脉粥样硬化症、肥胖症和痛风。
NLRP3在中枢神经系统疾病中的作用是新兴的,并且肺部疾病也已显示受NLRP3影响。此外,NLRP3在肝病、肾病和衰老的发展中具有作用。许多这些关联是使用Nlrp3-/-小鼠定义,但也深刻洞察到NLRP3在这些疾病中的特定活化。在2型糖尿病(T2D)中胰腺中胰岛淀粉样蛋白多肽的沉积活化NLRP3和IL-1β信号传导,从而导致细胞死亡和炎症。
若干小分子已显示出抑制NLRP3炎性体。响应于NLRP3而非NLRC4或NLRP1的活化,格列本脲(Glyburide)以微摩尔浓度抑制IL-1β产生。其它先前表征的弱NLRP3抑制剂包括小白菊内酯(parthenolide)、3,4-亚甲二氧基-β-硝基苯乙烯和二甲亚砜(DMSO),但这些剂具有有限效力且为非特异性的。
NLRP3相关疾病的当前治疗包括靶向IL-1的生物剂。这些为重组IL-1受体拮抗剂阿那白滞素(anakinra)、中和IL-1β抗体卡那单抗(canakinumab)和可溶性诱饵IL-1受体利纳西普(rilonacept)。这些方法已证实成功治疗CAPS,且这些生物剂已用于其它IL-1β相关疾病的临床试验中。
已一些将含二芳基磺酰脲的化合物鉴定为细胞因子释放抑制药物(CRID)(Perregaux等人,J Pharmacol Exp Ther,299:187-197,2001)。CRID为一类含二芳基磺酰脲的化合物,其抑制IL-1β的翻译后加工。IL-1β的翻译后加工伴有胱天蛋白酶-1的活化和细胞死亡。CRID遏制活化的单核细胞以使得胱天蛋白酶-1保持无活性且保留质膜潜伏期。
还公开了某些含有磺酰脲的化合物作为NLRP3的抑制剂(参见例如,Baldwin等人,J.Med.Chem.,59(5),1691-1710,2016;和WO 2016/131098 A1、WO 2017/129897 A1、WO2017/140778 A1、WO 2017/184623 A1、WO 2017/184624 A1、WO 2018/015445 A1、WO 2018/136890 A1、WO 2018/215818 A1、WO 2019/008025 A1、WO 2019/008029 A1、WO 2019/034686 A1、WO 2019/034688 A1、WO 2019/034690 A1、WO 2019/034692 A1、WO 2019/034693 A1、WO 2019/034696 A1、WO 2019/034697 A1、WO 2019/043610 A1、WO 2019/092170 A1、WO 2019/092171 A1和WO 2019/092172 A1)。另外,WO 2017/184604 A1和WO2019/079119 A1公开多种含磺酰胺的化合物作为NLRP3的抑制剂。还公开了某些含磺酰亚胺的化合物作为NLRP3的抑制剂(WO 2018/225018 A1、WO 2019/023145 A1、WO 2019/023147 A1和WO 2019/068772 A1)。
然而,NLRP3抑制剂的确切作用机理是未知的。
在形成炎性体的人类NLRP蛋白质中ATP结合结构域的生物化学和结构方面论述于Macdonald,J.A.等人(IUBMB Life.2013.65(10):851-862)中。
综上所述,一般来说,所有NLRP的特征在于N端热蛋白结构域、富含C端亮氨酸的重复序列和中心核苷酸结合结构域(NBD)。NBD由NACHT结构域和NAD(NACHT相关结构域)区域构成且由通过连接头区域连接的三个螺旋子结构域组成。NACHT因其在神经元细胞凋亡抑制蛋白((NAIP);主要组织相容复合物II类转录活化子(CIITA);来自真菌鹅掌柄孢壳(Podospora anserine)的不相容蛋白基因座(HET-E);和哺乳动物端粒酶相关蛋白)中的外观而被如此命名。
NACHT结构域的ATP结合和水解特性对NLRP在与多种细胞活性相关的ATP酶(AAA1)超家族的STAND子族内的分类很重要。结构域由若干不同的保守基序组成,包括Mg21协调环(coordination loop)和ATP酶特异性P-环。结构域的中心是存在区分NLRP与其它P-环NTP酶的Walker A和Walker B基序。
Walker A和Walker B基序为已知具有高度保守的3维结构的蛋白质序列基序。
Walker A基序与磷酸酯结合相关。Walker B基序为大多数位于A基序下游的P-环蛋白质中的基序。
需要确定NLRP3炎性体的抑制剂如何抑制NLRP3活化,并且鉴定NLRP3结合位点。
还需要鉴定且提供与NLRP3结合位点结合的化合物。
发明内容
本发明的第一方面提供一种NLRP3炎性体的结合位点,其中所述结合位点:
(a)在NLRP3炎性体的Walker A和/或Walker B位点处或附近;和/或
(b)包含一个或多个选自以下的残基:Arg183、Gly229、Ile230、Gly231、Lys232、Thr233、Ile234、Gly303、Asp305、Glu306、Leu413和His522。
在本发明的第一方面的一个实施方案中,结合位点在NLRP3炎性体的Walker A和/或Walker B位点处或附近。在一个实施方案中,结合位点在NLRP3炎性体的Walker A位点处或附近。
在本发明的第一方面的一个实施方案中,结合位点包含2个或更多个(或3个或更多个、或4个或更多个、或5个或更多个、或6个或更多个、或7个或更多个、或8个或更多个、或9个或更多个、或10个或更多个、或11个或更多个或全部12个)选自以下的残基:Arg183、Gly229、Ile230、Gly231、Lys232、Thr233、Ile234、Gly303、Asp305、Glu306、Leu413和His522。
在本发明的第一方面的另一实施方案中,结合位点还包含一个或多个(或2个或更多个、或3个或更多个、或4个或更多个、或5个或更多个、或6个或更多个、或7个或更多个、或8个或更多个、或9个或更多个、或10个或更多个、或11个或更多个、或12个或更多个、或13个或更多个、或14个或更多个、或15个或更多个或全部16个)选自以下的残基:Gln149、Cys150、Glu152、Asp153、Arg154、Asn155、Ala156、Arg157、Leu158、Glu160、Ser161、Val162、Ser163、Asp302、Trp416和Tyr565。
本发明的第二方面提供一种抑制NLRP3活化的方法,所述方法包括使化合物与本发明的第一方面的结合位点结合的步骤。本发明的第二方面还提供一种用于抑制NLRP3活化的化合物,其中所述化合物适于与本发明的第一方面的结合位点结合。
出于本发明的目的,其中据说化合物与结合位点“结合”,这包括化合物与结合位点之间的任何种类的相互作用,包括(但不限于)共价结合、非共价结合、可逆结合、离子结合、氢键合和范德华键合(Van der Waals bonding)。
本发明的第三方面提供一种治疗对NLRP3抑制有响应的疾病、病症或疾患的方法,所述方法包括使治疗有效量的化合物与本发明的第一方面的结合位点结合的步骤。本发明的第三方面还提供一种用于治疗对NLRP3抑制有响应的疾病、病症或疾患的化合物,其中所述化合物适于与本发明的第一方面的结合位点结合。本发明的第三方面还提供一种用于治疗对NLRP3抑制有响应的疾病、病症或疾患的化合物,其中所述化合物为本发明的第一方面的结合位点的拮抗剂。
在本发明的第三方面的一个实施方案中,所述疾病、病症或疾患选自:
(i)炎症;
(ii)自身免疫疾病;
(iii)癌症;
(iv)感染;
(v)中枢神经系统疾病;
(vi)代谢疾病;
(vii)心血管疾病;
(viii)呼吸疾病;
(ix)肝病;
(x)肾病;
(xi)眼部疾病;
(xii)皮肤病;
(xiii)淋巴疾患;
(xiv)心理障碍;
(xv)移植物抗宿主病;
(xvi)疼痛;
(xvii)与糖尿病相关的疾患;
(xviii)与关节炎相关的疾患;
(xix)头痛;
(xx)创伤或烧伤;和
(xxi)其中已确定个体携带NLRP3的种系或体细胞非沉默突变的任何疾病。
在本发明的第三方面的另一实施方案中,所述疾病、病症或疾患选自:
(i)隐热蛋白相关周期性综合征(CAPS);
(ii)穆-韦二氏综合征(Muckle-Wells syndrome;MWS);
(iii)家族性冷因性自身炎症综合征(FCAS);
(iv)新生儿发作型多系统炎症性疾病(NOMID);
(v)家族性地中海热(FMF);
(vi)化脓性关节炎、坏疽性脓皮病和痤疮综合征(PAPA);
(vii)高免疫球蛋白血症D和周期性发热综合征(HIDS);
(viii)肿瘤坏死因子(TNF)受体相关周期性综合征(TRAPS);
(ix)全身性幼年性特发性关节炎;
(x)成人发作型斯蒂尔氏病(adult-onset Still’s disease;AOSD);
(xi)复发性多软骨炎;
(xii)薛尼兹勒氏综合征(Schnitzler’s syndrome);
(xiii)斯维特氏综合征(Sweet’s syndrome);
(xiv)白塞氏病(Behcet’s disease);
(xv)抗合成酶综合征;
(xvi)白介素1受体拮抗剂缺乏症(DIRA);和
(xvii)A20单倍剂量不足(haploinsufficiency of A20;HA20)。
本发明的第四方面提供一种通过抑制NLRP3活化来减少细胞或线粒体活性氧物质(ROS)的方法,所述方法包括使化合物与本发明的第一方面的结合位点结合的步骤。本发明的第四方面还提供一种用于通过抑制NLRP3活化来减少细胞或线粒体活性氧物质(ROS)的化合物,其中所述化合物适于与本发明的第一方面的结合位点结合。
在本发明的第二、第三和第四方面的一个实施方案中,化合物为小分子(例如,小于1,000Da)、肽、多肽、寡核苷酸、蛋白质、抗体或适体。
在本发明的第二、第三和第四方面的另一实施方案中,化合物适于与结合位点共价或非共价(即,可逆地)结合。
在本发明的第二、第三和第四方面的另一实施方案中,化合物实现对NLRP3活化的抑制且由此防止ATP从NLRP3的Walker A和/或Walker B位点取代ADP。
在本发明的第二、第三和第四方面的另一实施方案中,化合物通过与一个或多个选自以下的残基结合而实现对NLRP3活化的抑制:Arg183、Gly229、Ile230、Gly231、Lys232、Thr233、Ile234、Gly303、Asp305、Glu306、Leu413和His522。在一个实施方案中,化合物通过与2个或更多个(或3个或更多个、或4个或更多个、或5个或更多个、或6个或更多个、或7个或更多个、或8个或更多个、或9个或更多个、或10个或更多个、或11个或更多个或全部12个)选自以下的残基结合而实现对NLRP3活化的抑制:Arg183、Gly229、Ile230、Gly231、Lys232、Thr233、Ile234、Gly303、Asp305、Glu306、Leu413和His522。在另一实施方案中,化合物通过与一个或多个(或2个或更多个、或3个或更多个、或4个或更多个、或5个或更多个、或6个或更多个、或7个或更多个、或8个或更多个、或9个或更多个、或10个或更多个、或11个或更多个、或12个或更多个、或13个或更多个、或14个或更多个、或15个或更多个或全部16个)选自以下的残基进一步结合而实现对NLRP3活化的抑制:Gln149、Cys150、Glu152、Asp153、Arg154、Asn155、Ala156、Arg157、Leu158、Glu160、Ser161、Val162、Ser163、Asp302、Trp416和Tyr565。
在本发明的第二、第三和第四方面的另一实施方案中,化合物包含充当膦酸酯模拟物的基序。举例来说,化合物可以是亚砜、磺酰亚胺、磺酰基乙酰胺、磺酰胺、氨基甲酸酯、磺酰基氨基甲酸酯、脲、磺酰基脲或磺酰基三唑。
本发明的第五方面提供一种筛选化合物的方法,所述方法包括以下步骤:(i)使化合物暴露于本发明的第一方面的结合位点,和(ii)测定化合物与结合位点的结合程度。
在本发明的第五方面的一个实施方案中,化合物与结合位点的结合程度通过质谱、NMR(核磁共振)、X射线晶体学、SPR(表面等离子体共振)或放射性配体结合来测定。
在本发明的第五方面的另一实施方案中,使用计算机进行筛选的方法。因此,本发明的第五方面还提供一种筛选化合物的方法,所述方法包括以下步骤:(i)在计算机上模拟使化合物暴露于本发明的第一方面的结合位点,和(ii)测定化合物与结合位点的结合程度。
本发明的第六方面提供一种通过本发明的第五方面的筛选方法鉴定的化合物,或其药学上可接受的盐、溶剂合物或前药。
本发明的第七方面提供一种适于与本发明的第一方面的结合位点结合的化合物,或其药学上可接受的盐、溶剂合物或前药。
本发明的化合物可以其游离碱形式和其酸加成盐形式使用。出于本发明的目的,本发明的化合物的“盐”包括酸加成盐。酸加成盐优选为与合适酸的药学上可接受的无毒性加成盐,所述酸包括(但不限于)无机酸,例如氢卤酸(例如,氢氟酸、氢氯酸、氢溴酸或氢碘酸)或其它无机酸(例如,硝酸、高氯酸、硫酸或磷酸);或有机酸,例如有机羧酸(例如,丙酸、丁酸、乙醇酸、乳酸、杏仁酸、柠檬酸、乙酸、苯甲酸、水杨酸、丁二酸、苹果酸或羟基丁二酸、酒石酸、反丁烯二酸、顺丁烯二酸、羟基顺丁烯二酸、粘液酸或半乳糖二酸、葡萄糖酸、泛酸或双羟萘酸)、有机磺酸(例如,甲磺酸、三氟甲磺酸、乙磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸(toluene-p-sulfonic acid)、萘-2-磺酸或樟脑磺酸)或氨基酸(例如,鸟氨酸、谷氨酸或天冬氨酸)。酸加成盐可为单酸加成盐、二酸加成盐、三酸加成盐或多酸加成盐。优选的盐为氢卤酸、硫酸、磷酸或有机酸加成盐。优选的盐为氢氯酸加成盐。
在本发明化合物包括季铵基团的情况下,通常化合物以其盐形式使用。季铵基团的抗衡离子可为任何药学上可接受的无毒性抗衡离子。合适抗衡离子的实例包括上文关于酸加成盐所论述的质子酸的共轭碱。
本发明的化合物还可以其游离酸形式和其加成盐形式使用。出于本发明的目的,本发明的化合物的“盐”包括在本发明的化合物的质子酸官能团(例如羧酸基)与合适阳离子之间形成的盐。合适的阳离子包括(但不限于)锂、钠、钾、镁、钙和铵。盐可为单盐、二盐、三盐或多盐。优选的盐为单锂盐、单钠盐、单钾盐、单镁盐、单钙盐或单铵盐或二锂盐、二钠盐、二钾盐、二镁盐、二钙盐或二铵盐。更优选的盐为单钠盐或二钠盐或单钾盐或二钾盐。
优选的任何盐为药学上可接受的无毒性盐。然而,除药学上可接受的盐以外,其它盐包括于本发明中,因为它们可能充当纯化或制备其它盐(例如药学上可接受的盐)中的中间物,或适用于鉴定、表征或纯化游离酸或游离碱。
本发明的化合物和/或盐可为无水的或呈水合物(例如,半水合物、单水合物、二水合物或三水合物)或其它溶剂合物的形式。这类其它溶剂合物可用常见有机溶剂形成,所述常见有机溶剂包括(但不限于)醇溶剂,例如甲醇、乙醇或异丙醇。
在本发明的一些实施方案中,提供治疗上无活性的前药。前药为当向受试者例如人类施用时完全或部分地转化成本发明化合物的化合物。在大多数实施方案中,前药为药理学上惰性的化学衍生物,其可在体内转化成活性药物分子以发挥治疗作用。本文所描述的化合物中的任一种可以前药形式施用,以增加化合物的活性、生物可用性或稳定性,或以其它方式改变化合物的特性。前药的典型实例包括在活性化合物的官能部分上具有生物学上不稳定的保护基的化合物。前药包括(但不限于)可以氧化、还原、胺化、脱胺化、羟基化、脱羟基化、水解、脱水解、烷基化、脱烷基化、酰基化、脱酰基化、磷酸化和/或脱磷酸化以产生活性化合物的化合物。本发明还涵盖如上文所描述的这类前药的盐和溶剂合物。
本发明的化合物、盐、溶剂合物和前药可含有至少一个手性中心。化合物、盐、溶剂合物和前药因此可以至少两种异构形式存在。本发明涵盖本发明的化合物、盐、溶剂合物和前药的外消旋混合物以及对映异构富集和基本上对映异构纯的异构体。出于本发明的目的,化合物的“基本上对映异构纯的”异构体包含小于5重量%的相同化合物的其它异构体,更通常小于2重量%,并且最通常小于0.5重量%。
本发明的化合物、盐、溶剂合物和前药可含有任何稳定同位素,包括(但不限于)12C、13C、1H、2H(D)、14N、15N、16O、17O、18O、19F和127I,以及任何放射性同位素,包括(但不限于)11C、14C、3H(T)、13N、15O、18F、123I、124I、125I和131I。
本发明的化合物、盐、溶剂合物和前药可以呈任何多晶或非晶形式。
本发明的第八方面提供一种药物组合物,其包含本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药,和药学上可接受的赋形剂。
用于选择和制备合适药物制剂的常规程序描述于例如“Aulton’sPharmaceutics-The Design and Manufacture of Medicines”,M.E.Aulton和K.M.G.Taylor,ChurchillLivingstone Elsevier,第4版,2013中。
可用于本发明的药物组合物中的药学上可接受的赋形剂(包括佐剂、稀释剂或载剂)为药物制剂领域中常规采用的那些赋形剂,且包括(但不限于)糖、糖醇、淀粉、离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如人类血清白蛋白)、缓冲物质(例如磷酸盐)、甘油、山梨酸、山梨酸钾、饱和蔬菜脂肪酸的偏甘油酯混合物、水、盐或电解质(例如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。
在一个实施方案中,本发明的第八方面的药物组合物另外包含一种或多种其它活性剂。
在另一实施方案中,本发明的第八方面的药物组合物可提供为成套药盒的一部分,其中所述成套药盒包含本发明的第八方面的药物组合物和一种或多种其它药物组合物,其中所述一种或多种其它药物组合物各自包含药学上可接受的赋形剂和一种或多种其它活性剂。
本发明的第九方面提供本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药或本发明的第八方面的药物组合物,其用于药物中,和/或用于治疗或预防疾病、病症或疾患。通常,用途包括向受试者施用化合物、盐、溶剂合物、前药或药物组合物。在一个实施方案中,用途包括共施用一种或多种其它活性剂。
如本文所使用的术语“治疗”同样是指治愈性疗法及改善或姑息性疗法。术语包括获得可在临床上建立或可不在临床上建立的有益或所要生理结果。有益或所要临床结果包括(但不限于)缓解症状、预防症状、减轻疾病程度、稳定(即,不恶化)疾患、延迟或减缓疾患/症状的进展/恶化、改善或缓和疾患/症状以及缓解(无论是部分还是全部),无论是可检测还是不可检测的。如本文中所使用,术语“缓和”和其变化形式意指与不施用本发明的化合物、盐、溶剂合物、前药或药物组合物相比,减轻生理疾患或症状的程度和/或非所要表现和/或减缓或延长进展的时程。如本文关于疾病、病症或疾患所使用的术语“预防”涉及防治性或预防性疗法以及降低罹患疾病、病症或疾患的风险的疗法。术语“预防”包括避免疾病、病症或疾患的出现和延迟疾病、病症或病况的发作。可将如通过受控临床试验所测量的任何统计学上显著(p≤0.05)的避免出现、延迟发作或风险降低视为预防疾病、病症或疾患。能够预防的受试者包括处于如通过遗传或生化标记物鉴定的疾病、病症或疾患的高风险下的那些受试者。通常,遗传或生化标记物适合于所考虑的疾病、病症或疾患,并且可包括例如在炎症的情况下的炎症性生物标记物,例如C-反应蛋白(CRP)和单核细胞趋化蛋白1(MCP-1);在NAFLD和NASH的情况下的总胆固醇、甘油三酯、胰岛素抗性和C-肽;和更一般来说在对NLRP3抑制有响应的疾病、病症或疾患的情况下的IL-1β和IL-18。
本发明的第十方面提供本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药的用途,其用于制造用于治疗或预防疾病、病症或疾患的药剂。通常,治疗或预防包括向受试者施用化合物、盐、溶剂合物、前药或药剂。在一个实施方案中,治疗或预防包括共施用一种或多种其它活性剂。
本发明的第十一方面提供一种治疗或预防疾病、病症或疾患的方法,所述方法包括以下步骤:施用有效量的本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药或本发明的第八方面的药物组合物,以由此治疗或预防疾病、病症或疾患。在一个实施方案中,方法还包括共施用有效量的一种或多种其它活性剂的步骤。通常,向有需要的受试者进行施用。
本发明的第十二方面提供本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药或本发明的第八方面的药物组合物,其用于治疗或预防个体的疾病、病症或疾患,其中所述个体具有NLRP3的种系或体细胞非沉默突变。突变可以是例如引起NLRP3活性增加的功能获得突变或其它突变。通常,用途包括向个体施用化合物、盐、溶剂合物、前药或药物组合物。在一个实施方案中,用途包括共施用一种或多种其它活性剂。用途还可包括诊断具有NLRP3的种系或体细胞非沉默突变的个体,其中基于突变的阳性诊断向个体施用化合物、盐、溶剂合物、前药或药物组合物。通常,可以通过任何合适的遗传或生物化学手段来进行个体中NLRP3的突变的鉴定。
本发明的第十三方面提供本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药,其用于制造用于治疗或预防个体的疾病、病症或疾患的药剂,其中个体具有NLRP3的种系或体细胞非沉默突变。突变可以是例如引起NLRP3活性增加的功能获得突变或其它突变。通常,治疗或预防包括向个体施用化合物、盐、溶剂合物、前药或药剂。在一个实施方案中,治疗或预防包括共施用一种或多种其它活性剂。治疗或预防还可包含诊断具有NLRP3的种系或体细胞非沉默突变的个体,其中基于突变的阳性诊断向个体施用化合物、盐、溶剂合物、前药或药剂。通常,可以通过任何合适的遗传或生物化学手段来进行个体中NLRP3的突变的鉴定。
本发明的第十四方面提供一种治疗或预防疾病、病症或疾患的方法,所述方法包括以下步骤:诊断具有NLRP3的种系或体细胞非沉默突变的个体,和向阳性诊断的个体施用有效量的本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药或本发明的第八方面的药物组合物,以由此治疗或预防疾病、病症或疾患。在一个实施方案中,方法还包括共施用有效量的一种或多种其它活性剂的步骤。通常,向有需要的受试者进行施用。
在一般实施方案中,疾病、病症或疾患可为免疫系统、心血管系统、内分泌系统、胃肠道、肾系统、肝系统、代谢系统、呼吸系统、中枢神经系统的疾病、病症或疾患,可为癌症或其它恶性病,和/或可由病原体所引起与病原体相关。
应了解,根据疾病、病症和疾患的广泛类别定义的这些一般实施方案不为相互排斥的。在这点上,可根据超过一个上述一般实施方案来分类任何特定疾病、病症或疾患。非限制性实例为I型糖尿病,其为自身免疫疾病和内分泌系统疾病。
在本发明的第九到第十四方面的一个实施方案中,疾病、病症或疾患对NLRP3抑制有响应。如本文中所使用,术语“NLRP3抑制”是指完全或部分降低NLRP3的活性水平且包括例如抑制活性NLRP3和/或抑制NLRP3的活化。
存在针对NLRP3诱导的IL-1和IL-18在与多种不同病症有关或由于多种不同病症而发生的炎症反应中的作用的证据(Menu等人,Clinical and Experimental Immunology,166:1-15,2011;Strowig等人,Nature,481:278-286,2012)。
已表明NLRP3的作用的遗传性疾病包括镰状细胞病(Vogel等人,Blood,130(增刊1):2234,2017)和含缬酪肽的蛋白质疾病(Valosin Containing Protein disease)(Nalbandian等人,Inflammation,40(1):21-41,2017)。
NLRP3已涉及多种自身炎症性疾病,包括家族性地中海热(FMF)、TNF受体相关周期性综合征(TRAPS)、高免疫球蛋白血症D和周期性发热综合征(HIDS)、化脓性关节炎、坏疽性脓皮病和痤疮(PAPA)、斯维特氏综合征、慢性非细菌性骨髓炎(CNO)和寻常痤疮(Cook等人,Eur J Immunol,40:595-653,2010)。特定来说,已发现NLRP3突变负责一组称为CAPS的罕见自身炎症性疾病(Ozaki等人,J Inflammation Research,8:15-27,2015;Schroder等人,Cell,140:821-832,2010;和Menu等人,Clinical and Experimental Immunology,166:1-15,2011)。CAPS为以复发性发热和炎症为特征的可遗传疾病,且由形成临床连续体的三种自身炎症性病症组成。为了增加严重程度,这些疾病为家族性冷因性自身炎症综合征(FCAS)、穆-韦二氏综合征(MWS)和慢性婴儿皮肤神经关节综合征(CINCA;也称为新生儿发作型多系统炎症性疾病(NOMID)),并且所有疾病都已显示为由NLRP3基因的功能获得突变引起,这导致IL-1β的分泌增加。
已显示多种自身免疫疾病涉及NLRP3,特定来说,包括多发性硬化症、1型糖尿病(T1D)、牛皮癣、类风湿性关节炎(RA)、白塞氏病、薛尼兹勒氏综合征、巨噬细胞活化综合征、乳糜泻(Masters,Clin Immunol,147(3):223-228,2013;Braddock等人,Nat Rev DrugDisc,3:1-10,2004;Inoue等人,Immunology,139:11-18,2013;Coll等人,Nat Med,21(3):248-55,2015;Scott等人,Clin Exp Rheumatol,34(1):88-93,2016;Pontillo等人,Autoimmunity,43(8):583-589,2010;和Guo等人,Clin Exp Immunol,194(2):231-243,2018)、全身性红斑狼疮(Lu等人,J Immunol,198(3):1119-29,2017)(包括狼疮肾炎(Zhao等人,Arthritis and Rheumatism,65(12):3176-3185,2013))、多发性硬化症(Xu等人,JCell Biochem,120(4):5160-5168,2019)和全身性硬化症(Artlett等人,ArthritisRheum,63(11):3563-74,2011)。
还显示NLRP3在多种呼吸疾病和肺疾病中起作用,包括慢性阻塞性肺病(COPD)、哮喘(包括类固醇抗性哮喘和嗜酸性粒细胞性哮喘)、支气管炎、石棉沉着病、火山灰诱导的炎症和硅肺病(Cassel等人,Proceedings of the National Academy of Sciences,105(26):9035-9040,2008;Chen等人,ERJ Open Research,4:00130-2017,2018;Chen等人,Toxicological Sciences,170(2):462-475,2019;Damby等人,Front Immun,8:2000,2018;De Nardo等人,Am J Pathol,184:42-54,2014;Lv等人,J Biol Chem,293(48):18454,2018;和Kim等人,Am J Respir Crit Care Med,196(3):283-97,2017)。
还表明NLRP3在多种中枢神经系统疾患中具有作用,包括帕金森氏病(Parkinson’s disease;PD)、阿尔茨海默氏病(AD)、痴呆、亨廷顿氏病(Huntington’s disease)、脑型疟疾、肺炎球菌脑膜炎引起的脑损伤(Walsh等人,Nature Reviews,15:84-97,2014;Cheng等人,Autophagy,1-13,2020;Couturier等人,J Neuroinflamm,13:20,2016;和Dempsey等人,Brain Behav Immun,61:306-316,2017)、颅内动脉瘤(Zhang等人,J Stroke&Cerebrovascular Dis,24(5):972-979,2015)、脑内出血(ICH)(Ren等人,Stroke,49(1):184-192,2018)、大脑局部缺血-再灌注损伤(Fauzia等人,Front Pharmacol,9:1034,2018;Hong等人,Neural Plasticity,2018:8,2018;Ye等人,Experimental Neurology,292:46-55,2017)、全身麻醉神经炎症(Fan等人,Front Cell Neurosci,12:426,2018)、败血症相关脑病变(SAE)(Fu等人,Inflammation,42(1):306-318,2019)、包括术后认知功能障碍(POCD)的围手术期神经认知障碍(Fan等人,Front Cell Neurosci,12:426,2018;和Fu等人,International Immunopharmacology,82:106317,2020)、早期脑损伤(蛛网膜下出血SAH)(Luo等人,Brain Res Bull,146:320-326,2019)和创伤性脑损伤(Ismael等人,JNeurotrauma,35(11):1294-1303,2018;和Chen等人,Brain Research,1710:163-172,2019)。
还显示NRLP3活性涉及各种代谢疾病,包括2型糖尿病(T2D)、动脉粥样硬化症、肥胖症、痛风、假性痛风、代谢综合征(Wen等人,Nature Immunology,13:352-357,2012;Duewell等人,Nature,464:1357-1361,2010;Strowig等人,Nature,481:278-286,2012)和非酒精性脂肪性肝炎(NASH)(Mridha等人,J Hepatol,66(5):1037-46,2017)。
还在以下中表明通过IL-1β对NLRP3的作用:动脉粥样硬化症(Chen等人,Journalof the American Heart Association,6(9):e006347,2017;和Chen等人,BiochemBiophys Res Commun,495(1):382-387,2018)、心肌梗塞(van Hout等人,Eur Heart J,38(11):828-36,2017)、心血管疾病(Janoudi等人,European Heart Journal,37(25):1959-1967,2016)、心肌肥大和纤维化(Gan等人,Biochim Biophys Acta,1864(1):1-10,2018)、心脏衰竭(Sano等人,J Am Coll Cardiol,71(8):875-66,2018)、主动脉瘤和夹层(Wu等人,Arterioscler Thro mb Vase Biol,37(4):694-706,2017)、由代谢功能障碍诱导的心脏损伤(Pavillard等人,Oncotarget,8(59):99740-99756,2017;和Zhang等人,Biochimica etBiophysica Acta,1863(6):1556-1567,2017)、心房颤动(Yao等人,Circulation,138(20):2227-2242,2018)、高血压(Gan等人,Biochim Biophys Acta,1864(1):1-10,2018)和其它心血管事件(Ridker等人,N Engl J Med,doi:10.1056/NEJMoa1707914,2017)。
已显示NLRP3所涉及的其它疾病、病症和疾患包括:
-眼部疾病,例如湿性和干性年龄相关的黄斑变性(Doyle等人,Nature Medicine,18:791-798,2012;和Tarallo等人,Cell,149(4):847-59,2012)、糖尿病性视网膜病变(Loukovaara等人,Acta Ophthalmol,95(8):803-808,2017)和视神经损伤(Puyang等人,Sci Rep,6:20998,2016年2月19日);
-肝病,包括非酒精性脂肪性肝炎(NASH)(Henao-Meija等人,Nature,482:179-185,2012)、肝脏的局部缺血再灌注损伤(Yu等人,Transplantation,103(2):353-362,2019)、爆发性肝炎(Pourcet等人,Gastroenterology,154(5):1449-1464,e20,2018)、肝纤维化(Zhang等人,Parasit Vectors,12(1):29,2019)和包括急性肝衰竭的肝衰竭(Wang等人,Hepatol Res,48(3):E194-E202,2018);
-肾病,包括肾钙质沉着症(Anders等人,Kidney Int,93(3):656-669,2018)、包括慢性晶体肾病变的肾纤维化(Ludwig-Portugall等人,Kidney Int,90(3):525-39,2016)、肥胖症相关的肾小球病变(Zhao等人,Mediators of Inflammation,论文3172647,2019)、急性肾损伤(Zhang等人,Diabetes,Metabolic Syndrome and Obesity:Targets andTherapy,12:1297-1309,2019)和肾高血压(Krishnan等人,Br J Pharmacol,173(4):752-65,2016;Krishnan等人,Cardiovasc Res,115(4):776-787,2019;Dinh等人,Aging,9(6):1595-1606,2017);
-与糖尿病相关的疾患,包括糖尿病性脑病变(Zhai等人,Molecules,23(3):522,2018)、糖尿病性视网膜病变(Zhang等人,Cell Death Dis,8(7):e2941,2017)、糖尿病性肾病变(也称为糖尿病性肾病)(Chen等人,BMC Complementary and Alternative Medicine,18:192,2018)和糖尿病低脂联素血症(Zhang等人,Biochimica et Biophysica Acta(BBA)-Molecular Basis of Disease,1863(6):1556-1567,2017);
-肺和皮肤的炎症反应(Primiano等人,J Immunol,197(6):2421-33,2016),包括肺局部缺血-再灌注损伤(Xu等人,Biochemical and Biophysical ResearchCommunications,503(4):3031-3037,2018)、上皮向间叶细胞转化(EMT)(Li等人,Experimental Cell Research,362(2):489-497,2018)、接触性超敏反应(例如大疱性类天疱疮(Fang等人,J Dermatol Sci,83(2):116-23,2016))、异位性皮炎(Niebuhr等人,Allergy,69(8):1058-67,2014)、化脓性汗腺炎(Alikhan等人,J Am Acad Dermatol,60(4):539-61,2009)、寻常痤疮(Qin等人,J Invest Dermatol,134(2):381-88,2014)和结节病(Jager等人,Am J Respir Crit Care Med,191:A5816,2015);
-关节的炎症反应(Braddock等人,Nat Rev Drug Disc,3:1-10,2004)和骨关节炎(Jin等人,PNAS,108(36):14867-14872,2011);
-与关节炎相关的疾患,包括关节炎发热(Verma,Linkoping University MedicalDissertations,第1250期,2011);
-肌肉萎缩性侧索硬化症(Gugliandolo等人,Inflammation,41(1):93-103,2018);
-囊性纤维化(Iannitti等人,Nat Commun,7:10791,2016);
-中风(Walsh等人,Nature Reviews,15:84-97,2014;Ye等人,ExperimentalNeurology,292:46-55,2017);
-头痛,包括偏头痛(He等人,Journal of Neuroinflammation,16:78,2019);
-慢性肾病(Granata等人,PLoS One,10(3):e0122272,2015);
-休格连氏综合征(Sjogren’s syndrome)(Vakrakou等人,Journal ofAutoimmunity,91:23-33,2018);
-移植物抗宿主病(Takahashi等人,Scientific Reports,7:13097,2017);
-镰状细胞病(Vogel等人,Blood,130(增刊1):2234,2017);和
-结肠炎和炎性肠病,包括溃疡性结肠炎和克罗恩氏病(Crohn’s disease)(Braddock等人,Nat Rev Drug Disc,3:1-10,2004;Neudecker等人,J Exp Med,214(6):1737-52,2017;Wu等人,Mediators Inflamm,2018:3048532,2018;和Lazaridis等人,DigDis Sci,62(9):2348-56,2017)和败血症(肠道上皮破坏)(Zhang等人,Dig Dis Sci,63(1):81-91,2018)。
已显示NLRP3的基因消融保护免受HSD(高糖饮食)、HFD(高脂肪饮食)和HSFD诱导的肥胖症(Pavillard等人,Oncotarget,8(59):99740-99756,2017)。
已发现NLRP3炎性体响应于氧化应激、晒伤(Hasegawa等人,Biochemical andBiophysical Research Communications,477(3):329-335,2016)和UVB照射(Schroder等人,Science,327:296-300,2010)而活化。
还显示NLRP3涉及炎症性痛觉过敏(Dolunay等人,Inflammation,40:366-386,2017)、伤口愈合(Ito等人,Exp Dermatol,27(1):80-86,2018)、烧伤愈合(Chakraborty等人,Exp Dermatol,27(1):71-79,2018)、疼痛(包括异常疼痛、多发性硬化症相关的神经痛)(Khan等人,Inflammopharmacology,26(1):77-86,2018)、慢性骨盆疼痛(Zhang等人,Prostate,79(12):1439-1449,2019)和癌症诱导的骨痛(Chen等人,PharmacologicalResearch,147:104339,2019)以及与早产相关的羊膜内炎症/感染(Faro等人,BiolReprod,100(5):1290-1305,2019;和Gomez-Lopez等人,Biol Reprod,100(5):1306-1318,2019)。
炎性体(且具体地说,NLRP3)也被提议作为通过多个病原体进行调节的靶标,所述病原体包括细菌病原体,例如金黄色葡萄球菌(Staphylococcus aureus)(包括耐甲氧西林金黄色葡萄球菌)(methicillin-resistant Staphylococcus aureus;MRSA)(Cohen等人,Cell Reports,22(9):2431-2441,2018;和Robinson等人,JCI Insight,3(7):e97470,2018)、结核分枝杆菌(Mycobacterium tuberculosis;TB)(Subbarao等人,ScientificReports,10:3709,2020)、蜡样芽孢杆菌(bacillus cereus)(Mathur等人,Nat Microbiol,4:362-374,2019)、鼠伤寒沙门氏菌(salmonella typhimurium)(Diamond等人,Sci Rep,7(1):6861,2017)和A群链球菌(LaRock等人,Science Immunology,1(2):eaah3539,2016);病毒,例如DNA病毒(Amsler等人,Future Virol,8(4):357-370,2013)、甲型流感病毒(Coates等人,Front Immunol,8:782,2017)、基孔肯雅(chikungunya)病毒、罗斯河病毒(Ross river virus)和α病毒(Chen等人,Nat Microbiol,2(10):1435-1445,2017);真菌病原体,例如白色念珠菌(Candida albicans)(Tucey等人,mSphere,1(3),pii:e00074-16,2016);和其它病原体,例如刚地弓形虫(T.gondii)(Gov等人,J Immunol,199(8):2855-2864,2017)、蠕虫(Alhallaf等人,Cell Reports,23(4):1085-1098,2018)、利什曼原虫(leishmania)(Novais等人,PLoS Pathogens,13(2):e1006196,2017)和疟原虫(Strangward等人,PNAS,115(28):7404-7409,2018)。已显示需要NLRP3以用于有效控制病毒、细菌、真菌和蠕虫病原体传染(Strowig等人,Nature,481:278-286,2012)。NLRP3活性也与增加的对病毒感染的易感性相关,例如通过人类免疫缺陷病毒(HIV)(Pontillo等人,JAquir Immune Defic Syndr,54(3):236-240,2010)。共感染有HIV和结核分枝杆菌(TB)的患者当中早期死亡风险的增加也与NLRP3活性相关(Ravimohan等人,Open ForumInfectious Diseases,5(5):ofy075,2018)。
NLRP3已涉及许多癌症的发病机制(Menu等人,Clinical and ExperimentalImmunology,166:1-15,2011;和Masters,Clin Immunol,147(3):223-228,2013)。举例来说,若干前述研究已表明IL-1β在癌症侵袭、生长和癌转移中的作用,且用卡那单抗抑制IL-1β已显示在随机、双盲、安慰剂对照试验中降低肺癌的发病率和总癌症死亡率(Ridker等人,Lancet,S0140-6736(17)32247-X,2017)。NLRP3炎性体或IL-1β的抑制还显示抑制体外肺癌细胞的增殖和迁移(Wang等人,Oncol Rep,35(4):2053-64,2016),且NLRP3已显示抑制NK细胞介导的癌发生和癌转移的控制(Chow等人,Cancer Res,72(22):5721-32,2012)。NLRP3炎性体的作用已在骨髓发育不良综合征(Basiorka等人,Blood,128(25):2960-2975,2016)中以及在多个其它癌症的癌发生中表明,所述其它癌症包括神经胶质瘤(Li等人,AmJ Cancer Res,5(1):442-449,2015)、结肠癌(Allen等人,J Exp Med,207(5):1045-56,2010)、黑色素瘤(Dunn等人,Cancer Lett,314(1):24-33,2012)、乳癌(Guo等人,Scientific Reports,6:36107,2016)、炎症诱导的肿瘤(Allen等人,J Exp Med,207(5):1045-56,2010;和Hu等人,PNAS,107(50):21635-40,2010)、多发性骨髓瘤(Li等人,Hematology,21(3):144-51,2016)和头颈部鳞状细胞癌(Huang等人,J Exp Clin CancerRes,36(1):116,2017;和Chen等人,Cellular and Molecular Life Sciences,75:2045-2058,2018)。还显示NLRP3炎性体的活化介导肿瘤细胞对5-氟尿嘧啶的化学抗性(Feng等人,J Exp Clin Cancer Res,36(1):81,2017),且NLRP3炎性体在外周神经中的活化有助于化学疗法诱导的神经痛(Jia等人,Mol Pain,13:1-11,2017)。
因此,可根据本发明的第九到第十四方面治疗或预防上文所列的疾病、病症或疾患中的任一种。可对NLRP3抑制有响应且可根据本发明的第九到第十四方面治疗或预防的疾病、病症或疾患的特定实例包括:
(i)炎症,包括由于炎症性病症(例如自身炎症性疾病)而发生的炎症、由于非炎症性病症的症状而发生的炎症、由于感染而发生的炎症,或继发于创伤、损伤或自身免疫的炎症;
(ii)自身免疫疾病,例如急性播散性脑炎、爱迪生氏病(Addison’s disease)、强直性脊柱炎、抗磷脂抗体综合征(APS)、抗合成酶综合征、再生障碍性贫血、自体免疫性肾上腺炎、自身免疫性肝炎、自体免疫性卵巢炎、自体免疫性多腺衰竭、自体免疫性甲状腺炎、包括儿科乳糜泻的乳糜泻、克罗恩氏病、1型糖尿病(T1D)、古德帕斯彻综合征(Goodpasture’ssyndrome)、格雷夫斯病(Graves’disease)、吉兰-巴雷综合征(Guillain-Barre syndrome;GBS)、桥本氏病(Hashimoto’s disease)、特发性血小板减少性紫癜、川崎氏病(Kawasaki’sdisease)、包括全身性红斑狼疮(SLE)的红斑狼疮、包括原发性进行性多发性硬化症(PPMS)、继发性进行性多发性硬化症(SPMS)和复发性缓解性多发性硬化症(RRMS)的多发性硬化症(MS)、重症肌无力、视性眼阵挛肌阵挛综合征(opsoclonus myoclonus syndrome;OMS)、视神经炎、奥德氏甲状腺炎(Ord’s thyroiditis)、天疱疮、恶性贫血、多发性关节炎、原发性胆汁性肝硬化、类风湿性关节炎(RA)、牛皮癣性关节炎、幼年性特发性关节炎或斯蒂尔氏病(Still’s disease)、难治性痛风性关节炎、赖特综合征(Reiter’s syndrome)、休格连氏综合征、全身性硬化症、全身性结缔组织病症、高安氏动脉炎(Takayasu’sarteritis)、颞动脉炎、温热型自身免疫性溶血性贫血、韦格纳氏肉芽肿(Wegener’sgranulomatosis)、普秃症(alopecia universalis)、白塞氏病、查加斯氏病(Chagas’disease)、自主神经失调、子宫内膜异位、化脓性汗腺炎(HS)、间质性膀胱炎、神经性肌强直、牛皮癣、结节病、硬皮病、溃疡性结肠炎、薛尼兹勒氏综合征、巨噬细胞活化综合征、布劳综合征(Blau syndrome)、白斑病或外阴疼痛;
(iii)癌症,包括肺癌、胰腺癌、胃癌(gastric cancer)、骨髓发育不良综合征、包括急性淋巴细胞性白血病(ALL)和急性骨髓性白血病(AML)的白血病、肾上腺癌、肛门癌、基底细胞癌和鳞状细胞皮肤癌、头颈部鳞状细胞癌、胆管癌、膀胱癌、骨癌、脑和脊髓肿瘤、乳癌、子宫颈癌、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、慢性骨髓单核细胞性白血病(CMML)、结肠直肠癌、子宫内膜癌、食道癌、尤文肿瘤家族(Ewing family oftumour)、眼癌、胆囊癌、胃肠道类癌瘤、胃肠道间质瘤(GIST)、妊娠期滋养细胞疾病、神经胶质瘤、霍奇金淋巴瘤(Hodgkin lymphoma)、卡波西肉瘤(Kaposi sarcoma)、肾癌、喉癌和下咽癌、肝癌、肺类癌瘤、包括皮肤T细胞淋巴瘤的淋巴瘤、恶性间皮瘤、黑色素瘤皮肤癌、梅克尔细胞皮肤癌(Merkel cell skin cancer)、多发性骨髓瘤、鼻腔和副鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、口腔和口咽癌症、骨肉瘤、卵巢癌、阴茎癌、垂体肿瘤、前列腺癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、胃癌(stomach cancer)、睾丸癌、胸腺癌、包括未分化型甲状腺癌的甲状腺癌、子宫肉瘤、阴道癌、外阴癌、瓦尔登斯特伦巨球蛋白血症(Waldenstrom macroglobulinemia)和威尔姆氏肿瘤(Wilms tumour);
(iv)感染,包括病毒感染(例如,来自流感病毒、人类免疫缺陷病毒(HIV)、α病毒(例如,基孔肯雅病毒和罗斯河病毒)、黄病毒(例如,登革病毒(Dengue virus)和寨卡病毒(Zika virus))、疱疹病毒(例如,埃-巴二氏病毒(Epstein Barr virus)、巨细胞病毒、水痘-带状疱疹病毒(Varicella-zoster virus)和KSHV)、痘病毒(例如,牛痘病毒(经改良的安卡拉牛痘病毒(Modified vaccinia virus Ankara))和粘液瘤病毒)、腺病毒(例如腺病毒5)或乳头状瘤病毒)、细菌感染(例如,来自金黄色葡萄球菌(包括MRSA)、幽门螺旋杆菌(Helicobacter pylori)、炭疽杆菌(Bacillus anthracis)、蜡样芽孢杆菌(Bacilluscereus)、百日咳博德特氏菌(Bordatella pertussis)、类鼻疽伯克霍尔德菌(Burkholderia pseudomallei)、白喉棒状杆菌(Corynebacterium diptheriae)、破伤风杆菌(Clostridium tetani)、肉毒杆菌(Clostridium botulinum)、肺炎链球菌(Streptococcus pneumoniae)、酿脓链球菌(Streptococcus pyogenes)、单核细胞增生李斯特氏菌(Listeria monocytogenes)、流感嗜血杆菌(Hemophilusinfluenzae)、多杀性巴氏杆菌(Pasteurella multicida)、痢疾志贺氏菌(Shigella dysenteriae)、结核分枝杆菌(Mycobacterium tuberculosis)、麻风分枝杆菌(Mycobacterium leprae)、肺炎支原体(Mycoplasma pneumoniae)、人型支原体(Mycoplasma hominis)、脑膜炎奈瑟球菌(Neisseria meningitidis)、淋病奈瑟球菌(Neisseria gonorrhoeae)、立氏立克次氏体(Rickettsia rickettsii)、嗜肺军团菌(Legionella pneumophila)、肺炎克雷伯氏杆菌(Klebsiella pneumoniae)、绿脓杆菌(Pseudomonas aeruginosa)、疮疱丙酸杆菌(Propionibacterium acnes)、梅毒螺旋体(Treponema pallidum)、沙眼衣原体(Chlamydiatrachomatis)、霍乱弧菌(Vibrio cholerae)、鼠伤寒沙门氏菌(Salmonellatyphimurium)、伤寒沙门氏菌(Salmonella typhi)、伯氏疏螺旋体(Borreliaburgdorferi)、尿道致病性大肠杆菌(Uropathogenic Escherichia coli;UPEC)或鼠疫耶尔森菌(Yersinia pestis))、真菌感染(例如,来自念珠菌属(Candida species)或曲霉属(Aspergillus species))、原虫感染(例如,来自疟原虫属(Plasmodium)、巴贝虫属(Babesia)、贾第虫属(Giardia)、内阿米巴属(Entamoeba)、利什曼原虫属(Leishmania)或锥虫(Trypanosomes))、蠕虫感染(例如,来自裂体吸虫属(schistosoma)、蛔虫、绦虫或吸虫)、朊病毒感染,和与前述内容中的任一种(例如与HIV和结核分枝杆菌)的共感染;
(v)中枢神经系统疾病,例如帕金森氏病、阿尔茨海默氏病、痴呆、运动神经元病、亨廷顿氏病、脑型疟疾、由肺炎球菌脑膜炎引起的脑损伤、颅内动脉瘤、脑内出血、败血症相关脑病变、围手术期神经认知障碍、术后认知功能障碍、早期脑损伤、创伤性脑损伤、大脑局部缺血-再灌注损伤、中风、全身麻醉神经炎症和肌肉萎缩性侧索硬化症;
(vi)代谢疾病,例如2型糖尿病(T2D)、动脉粥样硬化症、肥胖症、痛风和假性痛风;
(vii)心血管疾病,例如高血压、局部缺血、再灌注损伤(包括MI后缺血性再灌注性损伤)、中风(包括局部缺血性中风)、短暂性缺血性发作、心肌梗塞(包括复发性心肌梗塞)、心脏衰竭(包括充血性心脏衰竭和射血分数保留型心力衰竭)、心肌肥大和纤维化、栓塞、动脉瘤(包括腹主动脉瘤)、代谢诱导的心脏损伤和心包炎(包括德雷斯勒氏综合征(Dressler’s syndrome));
(viii)呼吸疾病,包括慢性阻塞性肺病(COPD)、哮喘(例如,过敏性哮喘、嗜酸性粒细胞性哮喘和类固醇抗性哮喘)、石棉沉着病、硅肺病、火山灰诱导的炎症、纳米粒子诱导的炎症、囊性纤维化和特发性肺纤维化;
(ix)肝病,包括非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)(包括晚期纤维化阶段F3和F4)、酒精性脂肪性肝病(AFLD)、酒精性脂肪性肝炎(ASH)、肝脏的局部缺血再灌注损伤、爆发性肝炎、肝纤维化和肝衰竭(包括急性肝衰竭);
(x)肾病,包括慢性肾病、草酸盐肾病变、肾钙质沉着症、肾小球肾炎、糖尿病性肾病变、肥胖症相关的肾小球病变、肾纤维化(包括慢性晶体肾病变)、急性肾衰竭、急性肾损伤和肾高血压;
(xi)眼部疾病,包括眼部上皮的那些疾病、年龄相关的黄斑变性(AMD)(干性和湿性)、休格连氏综合征、葡萄膜炎、角膜感染、糖尿病性视网膜病变、视神经损伤、干眼和青光眼;
(xii)皮肤病,包括皮炎(例如接触性皮炎和异位性皮炎)、接触性超敏反应、牛皮癣、晒伤、皮损、化脓性汗腺炎(HS)、其它引起囊肿的皮肤病、坏疽性脓皮病和寻常痤疮(包括聚合性痤疮);
(xiii)淋巴疾患,例如淋巴管炎和卡斯尔曼氏病(Castleman’s disease);
(xiv)心理障碍,例如抑郁和心理压力;
(xv)移植物抗宿主病;
(xvi)疼痛,例如骨盆疼痛、痛觉过敏、异常疼痛(包括机械性异常疼痛)、神经痛(包括多发性硬化症相关的神经痛)和癌症诱导的骨痛;(xvii)与糖尿病相关的疾患,包括糖尿病性脑病变、糖尿病性视网膜病变、糖尿病性肾病变、糖尿病血管内皮功能障碍和糖尿病性低脂联素血症;
(xviii)与关节炎相关的疾患,包括关节炎发热;
(xix)头痛,包括丛集性头痛、特发性颅内高血压、偏头痛、低压头痛(例如后腰椎穿刺)、伴有结膜充血和撕裂的短暂单侧神经痛样头痛(Short-Lasting UnilateralNeuralgiform Headache With Conjunctival Injection and Tearing;SUNCT)和紧张型头痛;
(xx)创伤和烧伤,包括皮肤创伤和皮肤烧伤;和
(xxi)其中已确定个体携带NLRP3的种系或体细胞非沉默突变的任何疾病。
在一个实施方案中,疾病、病症或疾患选自:
(i)癌症;
(ii)感染;
(iii)中枢神经系统疾病;
(iv)心血管疾病;
(v)肝病;
(vi)眼部疾病;或
(vii)皮肤病。
更通常,疾病、病症或疾患选自:
(i)癌症;
(ii)感染;
(iii)中枢神经系统疾病;或
(iv)心血管疾病。
在一个实施方案中,疾病、病症或疾患选自:
(i)聚合性痤疮;
(ii)异位性皮炎;
(iii)阿尔茨海默氏病;
(iv)肌肉萎缩性侧索硬化症;
(v)年龄相关的黄斑变性(AMD);
(vi)未分化型甲状腺癌;
(vii)隐热蛋白相关周期性综合征(CAPS);
(viii)接触性皮炎;
(ix)囊性纤维化;
(x)充血性心脏衰竭;
(xi)慢性肾病;
(xii)克罗恩氏病;
(xiii)家族性冷因性自身炎症综合征(FCAS);
(xiv)亨廷顿氏病;
(xv)心脏衰竭;
(xvi)射血分数保留型心力衰竭;
(xvii)缺血性再灌注性损伤;
(xviii)幼年性特发性关节炎;
(xix)心肌梗塞;
(xx)巨噬细胞活化综合征;
(xxi)骨髓发育不良综合征;
(xxii)多发性骨髓瘤;
(xxiii)运动神经元病;
(xxiv)多发性硬化症;
(xxv)穆-韦二氏综合征;
(xxvi)非酒精性脂肪性肝炎(NASH);
(xxvii)新生儿发作型多系统炎症性疾病(NOMID);
(xxviii)帕金森氏病;
(xxix)镰状细胞病;
(xxx)全身性幼年性特发性关节炎;
(xxxi)全身性红斑狼疮;
(xxxii)创伤性脑损伤;
(xxxiii)短暂性缺血性发作;
(xxxiv)溃疡性结肠炎;或
(xxxv)含缬酪肽的蛋白质疾病。
在本发明的第九到第十四方面的另一实施方案中,治疗或预防包括对病毒感染的易感性降低。举例来说,治疗或预防可包括对HIV感染的易感性降低。
在本发明的另一典型实施方案中,疾病、病症或疾患为炎症。可根据本发明的第九到第十四方面治疗或预防的炎症的实例包括与以下有关或由于以下而发生的炎症反应:
(i)皮肤疾患,例如接触性超敏反应、大疱性类天疱疮、晒伤、牛皮癣、局部皮肤皮炎、接触性皮炎、过敏性接触性皮炎、脂溢性皮肤炎、扁平苔藓、硬皮病、天疱疮、大疱性表皮松懈、荨麻疹、红斑或秃发;
(ii)关节疾患,例如骨关节炎、全身性幼年性特发性关节炎、成人发作型斯蒂尔氏病、复发性多软骨炎、类风湿性关节炎、幼年性慢性关节炎、痛风或血清阴性脊柱关节病变(例如,强直性脊柱炎、牛皮癣性关节炎或莱特尔氏病(Reiter’s disease));
(iii)肌肉疾患,例如多发性肌炎或重症肌无力;
(iv)胃肠道疾患,例如炎症性肠病(包括克罗恩氏病和溃疡性结肠炎)、结肠炎、胃溃疡、乳糜泻、直肠炎、胰腺炎、嗜酸性胃肠炎、肥大细胞增多症、抗磷脂综合征或可具有远离肠道的影响的食物相关过敏(例如,偏头痛、鼻炎或湿疹);
(v)呼吸系统疾患,例如慢性阻塞性肺病(COPD)、哮喘(包括嗜酸性粒细胞性哮喘、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘或尘埃性哮喘,且尤其慢性或顽固性哮喘,例如晚期哮喘和气管高反应性)、支气管炎、鼻炎(包括急性鼻炎、过敏性鼻炎、萎缩性鼻炎、慢性鼻炎、干酪性鼻炎、肥厚性鼻炎、化脓性鼻炎(rhinitis pumlenta)、干燥性鼻炎、药物性鼻炎、膜性鼻炎、季节性鼻炎(例如花粉热)和血管舒缩性鼻炎)、鼻窦炎、特发性肺纤维化(IPF)、结节病、农民肺(farmer’s lung)、硅肺病、石棉沉着病、火山灰诱导的炎症、成人呼吸窘迫综合征、过敏性肺炎或特发性间质性肺炎;
(vi)血管疾患,例如动脉粥样硬化症、白塞氏病、血管炎或韦格纳氏肉芽肿;
(vii)自身免疫疾患,例如全身性红斑狼疮、休格连氏综合征、全身性硬化症、桥本氏甲状腺炎(Hashimoto’s thyroiditis)、I型糖尿病、特发性血小板减少性紫癜或格雷夫斯病(Graves disease);
(viii)眼部疾患,例如葡萄膜炎、过敏性结膜炎或春季结膜炎;
(ix)神经疾患,例如多发性硬化症或脑脊髓炎;
(x)感染或感染相关疾患,例如获得性免疫缺乏综合征(AIDS)、急性或慢性细菌感染、急性或慢性寄生虫感染、急性或慢性病毒感染、急性或慢性真菌感染、脑膜炎、肝炎(甲型、乙型或丙型或其它病毒性肝炎)、腹膜炎、肺炎、会厌炎、疟疾、出血性登革热(denguehemorrhagic fever)、利什曼体病(leishmaniasis)、链球菌性肌炎、结核分枝杆菌(包括结核分枝杆菌和HIV共感染)、胞内鸟分枝杆菌(mycobacterium avium intracellulare)、卡氏肺孢子虫肺炎(pneumocystis carinii pneumonia)、睾丸炎/副睾炎、军团杆菌(legionella)、莱姆病(Lyme disease)、甲型流感、埃-巴二氏病毒感染、病毒性脑炎/无菌性脑膜炎或盆腔炎症性疾病;
(xi)肾疾患,例如肾小球系膜增生性肾小球肾炎、肾病综合征、肾炎、肾小球肾炎、肥胖症相关的肾小球病变、急性肾衰竭、急性肾损伤、尿毒症、肾炎综合征(nephriticsyndrome)、肾纤维化(包括慢性晶体肾病变)或肾高血压;
(xii)淋巴疾患,例如卡斯尔曼氏病;
(xiii)免疫系统的疾患或涉及免疫系统的疾患,例如高IgE综合征、瘤型麻风病、家族性噬血细胞性淋巴组织细胞增生症或移植物抗宿主病;
(xiv)肝脏疾患,例如慢性活动性肝炎、非酒精性脂肪性肝炎(NASH)、酒精诱导的肝炎、非酒精性脂肪性肝病(NAFLD)、酒精性脂肪性肝病(AFLD)、酒精性脂肪性肝炎(ASH)、原发性胆汁性肝硬化症、爆发性肝炎、肝纤维化或肝衰竭;
(xv)癌症,包括上文所列的那些癌症;
(xvi)烧伤、创伤、外伤、出血或中风;
(xvii)辐射曝露;
(xviii)代谢疾病,例如2型糖尿病(T2D)、动脉粥样硬化症、肥胖症、痛风或假性痛风;和/或
(xix)疼痛,例如炎症性痛觉过敏、骨盆疼痛、异常疼痛、神经痛或癌症诱导的骨痛。
在本发明的第九到第十四方面的一个实施方案中,疾病、病症或疾患为自身炎症性疾病,例如隐热蛋白相关周期性综合征(CAPS)、穆-韦二氏综合征(MWS)、家族性冷因性自身炎症综合征(FCAS)、家族性地中海热(FMF)、新生儿发作型多系统炎症性疾病(NOMID)、肿瘤坏死因子(TNF)受体相关周期性综合征(TRAPS)、高免疫球蛋白血症D和周期性发热综合征(HIDS)、白介素1受体拮抗剂缺乏症(DIRA)、马吉德综合征(Majeed syndrome)、化脓性关节炎、坏疽性脓皮病和痤疮综合征(PAPA)、成人发作型斯蒂尔氏病(AOSD)、A20单倍剂量不足(HA20)、儿科肉芽肿性关节炎(PGA)、PLCG2相关抗体缺乏症和免疫失调(PLAID)、PLCG2相关自身炎症、抗体缺乏症和免疫失调(APLAID)或伴有B细胞免疫缺陷的铁粒幼细胞性贫血、周期性发热和发育迟缓(SIFD)。
上文列举了可对NLRP3抑制有响应且可根据本发明的第九到第十四方面治疗或预防的疾病、病症或疾患的实例。这些疾病、病症或疾患中的一些基本上或完全由NLRP3炎性体活性和NLRP3诱导的IL-1β和/或IL-18介导。因此,这类疾病、病症或疾患可尤其对NLRP3抑制有响应且可尤其适合用于根据本发明的第九到第十四方面的治疗或预防。这类疾病、病症或疾患的实例包括隐热蛋白相关周期性综合征(CAPS)、穆-韦二氏综合征(MWS)、家族性冷因性自身炎症综合征(FCAS)、新生儿发作型多系统炎症性疾病(NOMID)、家族性地中海热(FMF)、化脓性关节炎、坏疽性脓皮病和痤疮综合征(PAPA)、高免疫球蛋白血症D和周期性发热综合征(HIDS)、肿瘤坏死因子(TNF)受体相关周期性综合征(TRAPS)、全身性幼年性特发性关节炎、成人发作型斯蒂尔氏病(AOSD)、复发性多软骨炎、薛尼兹勒氏综合征、斯维特氏综合征、白塞氏病、抗合成酶综合征、白介素1受体拮抗剂缺乏症(DIRA)和A20单倍剂量不足(HA20)。
此外,上文所提及的一些疾病、病症或疾患由于NLRP3的突变而产生,具体地说,引起NLRP3活性增加。因此,这类疾病、病症或疾患可尤其对NLRP3抑制有响应且可尤其适合用于根据本发明的第九到第十四方面的治疗或预防。这类疾病、病症或疾患的实例包括隐热蛋白相关周期性综合征(CAPS)、穆-韦二氏综合征(MWS)、家族性冷因性自身炎症综合征(FCAS)和新生儿发作型多系统炎症性疾病(NOMID)。
本发明的第十五方面提供一种抑制NLRP3活化的方法,所述方法包括使用本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药或本发明的第八方面的药物组合物来抑制NLRP3活化。
在本发明的第十五方面的一个实施方案中,所述方法包括使用本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药或本发明的第八方面的药物组合物,以及一种或多种其它活性剂。
在本发明的第十五方面的一个实施方案中,离体或体外进行所述方法,例如以便分析NLRP3抑制对细胞的影响。
在本发明的第十五方面的另一实施方案中,体内进行所述方法。举例来说,所述方法可包括以下步骤:施用有效量的本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药或本发明的第八方面的药物组合物,以由此抑制NLRP3。在一个实施方案中,方法还包括共施用有效量的一种或多种其它活性剂的步骤。通常,向有需要的受试者进行施用。
替代地,本发明的第十五方面的方法可为一种抑制非人类动物受试者中的NLRP3的方法,所述方法包括以下步骤:向非人类动物受试者施用化合物、盐、溶剂合物、前药或药物组合物且任选地随后杀死或处死非人类动物受试者。通常,这种方法还包括分析来自任选地杀死或处死的非人类动物受试者的一个或多个组织或流体样品的步骤。在一个实施方案中,方法还包括共施用有效量的一种或多种其它活性剂的步骤。
本发明的第十六方面提供本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药或本发明的第八方面的药物组合物,其用于抑制NLRP3。通常,用途包括向受试者施用化合物、盐、溶剂合物、前药或药物组合物。在一个实施方案中,化合物、盐、溶剂合物、前药或药物组合物与一种或多种其它活性剂共施用。
本发明的第十七方面提供本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药的用途,其用于制造用于抑制NLRP3的药剂。通常,抑制包括向受试者施用化合物、盐、溶剂合物、前药或药剂。在一个实施方案中,化合物、盐、溶剂合物、前药或药剂与一种或多种其它活性剂共施用。
在包含使用或共施用一种或多种其它活性剂的本发明的第九到第十七方面中的任一个的任何实施方案中,所述一种或多种其它活性剂可包含例如一种、两种或三种不同的其它活性剂。
一种或多种其它活性剂可在彼此和/或在本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药或本发明的第八方面的药物组合物之前、同时、依序或之后使用或施用。在一种或多种其它活性剂与本发明的第六或第七方面的化合物或药学上可接受的盐、溶剂合物或前药同时施用的情况下,可施用本发明的第八方面的药物组合物,其中药物组合物另外包含一种或多种其它活性剂。
在包含使用或共施用一种或多种其它活性剂的本发明的第九到第十七方面中的任一个的一个实施方案中,一种或多种其它活性剂选自:
(i)化学治疗剂;
(ii)抗体;
(iii)烷化剂;
(iv)抗代谢物;
(v)抗血管生成剂;
(vi)植物碱和/或萜类;
(vii)拓扑异构酶抑制剂;
(viii)mTOR抑制剂;
(ix)芪类化合物;
(x)STING激动剂;
(xi)癌症疫苗;
(xii)免疫调节剂;
(xiii)抗生素;
(xiv)抗真菌剂;
(xv)抗蠕虫剂;和/或
(xvi)其它活性剂。
应了解,根据活性剂的广泛类别定义的这些一般实施方案不为相互排斥的。在这点上,可根据超过一个上述一般实施方案来分类任何特定活性剂。非限制性实例为乌瑞鲁单抗(urelumab),其为作为用于治疗癌症的免疫调节剂的抗体。
如应理解,在其它活性剂为小化学实体的情况下,在下文对特定小化学实体的任何提及应理解为涵盖特定小化学实体的所有盐、水合物、溶剂合物、多晶型和前药形式。类似地,在其它活性剂为生物制剂(例如单克隆抗体)的情况下,在下文对特定生物制剂的任何提及应理解为涵盖其所有生物类似物。
在一些实施方案中,一种或多种化学治疗剂选自乙酸阿比特龙(abirateroneacetate)、六甲蜜胺(altretamine)、安吖啶(amsacrine)、脱水长春碱(anhydrovinblastine)、奥瑞他汀(auristatin)、阿扎胞苷(azacitidine)、5-氮杂胞苷、硫唑嘌呤(azathioprine)、阿德力霉素(adriamycin)、贝沙罗汀(bexarotene)、比卡鲁胺(bicalutamide)、BMS 184476、博莱霉素(bleomycin)、硼替佐米(bortezomib)、N,N-二甲基-L-缬氨酰基-L-缬氨酰基-N-甲基-L-缬氨酰基-L-脯氨酰基-L-脯氨酸-叔丁酰胺、顺铂(cisplatin)、卡铂(carboplatin)、卡铂环磷酰胺(carboplatin cyclophosphamide)、苯丁酸氮芥(chlorambucil)、恶病质素(cachectin)、西马多丁(cemadotin)、环磷酰胺、卡莫司汀(carmustine)、克拉屈滨(cladribine)、念珠藻环肽(cryptophycin)、阿糖胞苷(cytarabine)、多西他赛(docetaxel)、多西他赛(doxetaxel)、小红莓(doxorubicin)、达卡巴嗪(dacarbazine)(DTIC)、放线菌素D(dactinomycin)、道诺霉素(daunorubicin)、地西他滨(decitabine)、海兔毒素(dolastatin)、依托泊苷(etoposide)、磷酸依托泊苷(etoposide phosphate)、恩杂鲁胺(enzalutamide)(MDV3100)、5-氟尿嘧啶、氟达拉滨(fludarabine)、氟他胺(flutamide)、吉西他滨(gemcitabine)、羟基脲和羟基脲紫杉烷(hydroxyureataxane)、艾达霉素(idarubicin)、异环磷酰胺(ifosfamide)、伊立替康(irinotecan)、伊沙佐米(ixazomib)、来那度胺(lenalidomide)、来那度胺-地塞米松(lenalidomide-dexamethasone)、甲酰四氢叶酸(leucovorin)、氯尼达明(lonidamine)、洛莫司汀(lomustine)(CCNU)、拉洛他赛(larotaxel)(RPR109881)、氮芥(mechlorethamine)、巯基嘌呤、甲氨蝶呤、丝裂霉素C(mitomycin C)、米托蒽醌(mitoxantrone)、美法仑(melphalan)、米伏布林(mivobulin)、3',4'-二脱氢-4'-脱氧-8'-去甲-长春花碱、尼鲁米特(nilutamide)、奥沙利铂(oxaliplatin)、奥那司酮(onapristone)、泼尼莫司汀(prednimustine)、丙卡巴肼(procarbazine)、太平洋紫杉醇(paclitaxel)、含铂抗癌剂、2,3,4,5,6-五氟-N-(3-氟-4-甲氧苯基)苯磺酰胺、泼尼莫司汀、丙卡巴肼、雷利米得(revlimid)、根霉素(rhizoxin)、塞尼氟(sertenef)、链脲霉素(streptozocin)、磷酸雌莫司汀(stramustine phosphate)、维甲酸(tretinoin)、他索纳明(tasonermin)、紫杉醇(taxol)、拓扑替康(topotecan)、他莫昔芬(tamoxifen)、替尼泊苷(teniposide)、紫杉烷(taxane)、喃氟啶(tegafur)/尿嘧啶(uracil)、沙立度胺(thalidomide)、长春新碱(vincristine)、长春碱(vinblastine)、长春瑞宾(vinorelbine)、长春地辛(vindesine)、硫酸长春地辛(vindesine sulfate)和/或长春氟宁(vinflunine)。
替代地或另外,一种或多种化学治疗剂可选自CD59补体片段、纤维结合蛋白片段、gro-β(CXCL2)、肝素酶、肝素六糖片段、人类绒膜促性腺激素(hCG)、I型干扰素配体(例如干扰素α和干扰素β)、I型干扰素模拟物、II型干扰素配体(例如干扰素γ)、II型干扰素模拟物、干扰素诱导蛋白(IP-10)、kringle 5(纤维蛋白溶酶原片段)、金属蛋白酶抑制剂(TIMP)、2-甲氧基雌二醇、胎盘核糖核酸酶抑制剂、纤维蛋白溶酶原活化因子抑制剂、血小板因子-4(PF4)、催乳素16kD片段、增殖蛋白相关蛋白质(proliferin-related protein;PRP)、各种类视黄素、四氢皮质醇-S、凝血栓蛋白-1(TSP-1)、转化生长因子-β(TGF-β)、血管抑制素、血管新生抑制素(钙网蛋白片段)、细胞因子(包括白介素,例如白介素-1、白介素-2、白介素-5、白介素-10、白介素-12和白介素-33)、白介素-1配体和模拟物(例如,利纳西普、阿那白滞素和阿那白滞素-地塞米松(anakinra-dexamethasone))、白介素-2配体和模拟物、白介素-5配体和模拟物、白介素-10配体和模拟物、白介素-12配体和模拟物,和/或白介素-33配体和模拟物。
在一些实施方案中,一种或多种抗体可包含一种或多种单克隆抗体。在一些实施方案中,一种或多种抗体为抗TNFα和/或抗IL-6抗体,具体地说抗TNFα和/或抗IL-6单克隆抗体。在一些实施方案中,一种或多种抗体选自阿巴西普(abatacept)、阿昔单抗(abciximab)、阿达木单抗(adalimumab)、阿仑单抗(alemtuzumab)、阿特珠单抗(atezolizumab)、阿特力珠单抗(atlizumab)、阿维鲁单抗(avelumab)、巴利昔单抗(basiliximab)、贝利单抗(belimumab)、贝那利珠单抗(benralizumab)、贝伐珠单抗(bevacizumab)、维多汀布妥昔单抗(bretuximab vedotin)、布罗达单抗(brodalumab)、卡那单抗、西妥昔单抗(cetuximab)、聚乙二醇赛妥珠单抗(ceertolizumab pegol)、达利珠单抗(daclizumab)、地诺单抗(denosumab)、杜匹鲁单抗(dupilumab)、度伐单抗(durvalumab)、依库珠单抗(eculizumab)、依法利珠单抗(efalizumab)、埃罗妥珠单抗(elotuzumab)、吉妥珠单抗(gemtuzumab)、戈利木单抗(golimumab)、古塞库单抗(guselkumab)、替坦异贝莫单抗(ibritumomab tiuxetan)、英利昔单抗(infliximab)、伊匹单抗(ipilimumab)、伊科奇单抗(ixekizumab)、美泊利单抗(mepolizumab)、莫罗莫那(muromonab)-CD3、那他珠单抗(natalizumab)、纳武单抗(nivolumab)、奥法木单抗(ofatumumab)、奥马珠单抗(omalizumab)、帕利珠单抗(palivizumab)、帕尼图单抗(panitumuab)、派姆单抗(pembrolizumab)、兰比珠单抗(ranibizumab)、瑞利珠单抗(reslizumab)、利桑库珠单抗(risankizumab)、利妥昔单抗(rituximab)、沙瑞卢单抗(sarilumab)、塞库金单抗(secukinumab)、思图昔单抗(siltuximab)、替德库珠单抗(tildrakizumab)、托西利单抗(tocilizumab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)和/或优特克单抗(ustekinumab)。
在一些实施方案中,一种或多种烷化剂可包含能够在存在于细胞(包括例如癌细胞)中的条件下使亲核官能团烷化的剂。在一些实施方案中,一种或多种烷化剂选自顺铂、卡铂、氮芥、环磷酰胺、苯丁酸氮芥、异环磷酰胺和/或奥沙利铂。在一些实施方案中,烷化剂可通过与生物学上重要的分子中的氨基、羧基、硫氢基和/或磷酸基形成共价键而削弱细胞功能来起作用。在一些实施方案中,烷化剂可通过修饰细胞的DNA来起作用。
在一些实施方案中,一种或多种抗代谢物可包含能够影响或防止RNA或DNA合成的剂。在一些实施方案中,一种或多种抗代谢物选自硫唑嘌呤和/或巯基嘌呤。
在一些实施方案中,一种或多种抗血管生成剂选自沙立度胺、来那度胺、内皮生长抑素、血管生成素抑制剂、血管生长抑制蛋白(angioarrestin)、血管生长抑素(纤维蛋白溶酶原片段)、基底膜胶原蛋白衍生的抗血管生成因子(肿瘤抑制素、血管能抑制素或抑制蛋白)、抗血管生成抗凝血酶III和/或软骨衍生的抑制剂(CDI)。
在一些实施方案中,一种或多种植物碱和/或萜类可预防微管功能。在一些实施方案中,一种或多种植物碱和/或萜类选自长春花生物碱(vinca alkaloid)、鬼臼毒素(podophyllotoxin)和/或紫杉烷。在一些实施方案中,一种或多种长春花生物碱可来源于马达加斯加长春花(Madagascar periwinkle)、长春花(Catharanthus roseus)(原名为玫瑰红长春花(Vinca rosea)),且可选自长春新碱、长春碱、长春瑞宾和/或长春地辛。在一些实施方案中,一种或多种紫杉烷选自紫杉醇、太平洋紫杉醇、多西他赛和/或奥他赛(ortataxel)。在一些实施方案中,一种或多种鬼臼毒素选自依托泊苷和/或替尼泊苷。
在一些实施方案中,一种或多种拓扑异构酶抑制剂选自I型拓扑异构酶抑制剂和/或II型拓扑异构酶抑制剂,且可通过干扰DNA超螺旋化来干扰DNA的转录和/或复制。在一些实施方案中,一种或多种I型拓扑异构酶抑制剂可包含喜树碱(camptothecin),其可选自依沙替康(exatecan)、伊立替康、勒托替康(lurtotecan)、拓扑替康、BNP 1350、CKD 602、DB67(AR67)和/或ST 1481。在一些实施方案中,一种或多种II型拓扑异构酶抑制剂可包含表鬼臼毒素(epipodophyllotoxin),其可选自安吖啶、依托泊苷、磷酸依托泊苷和/或替尼泊苷。
在一些实施方案中,一种或多种mTOR(雷帕霉素的哺乳动物靶标,亦称为雷帕霉素的机制靶标)抑制剂选自雷帕霉素(rapamycin)、依维莫司(everolimus)、坦罗莫司(temsirolimus)和/或德佛莫司(deforolimus)。
在一些实施方案中,一种或多种芪类化合物选自白藜芦醇(resveratrol)、白皮杉醇(piceatannol)、赤松素(pinosylvin)、蝶芪(pterostilbene)、α-葡萄素(alpha-viniferin)、蛇葡萄素(ampelopsin)A、蛇葡萄素E、二妥英酮素(diptoindonesin)C、二妥英酮素F、ε-葡萄素、葛藟葡萄醇(flexuosol)A、买麻藤素(gnetin)H、雪胆醇(hemsleyanol)D、霍毕酚(hopeaphenol)、反式-二妥英酮素B、白皮杉醇葡萄糖苷(astringin)、白藜芦醇苷(piceid)和/或二妥英酮素A。
在一些实施方案中,一种或多种STING(干扰素基因的刺激剂,亦称为跨膜蛋白(TMEM)173)激动剂可包含环状二核苷酸(CDN)(例如,c-di-AMP、c-di-GMP和cGAMP),和/或可包括以下修饰特征中的一种或多种的经修饰的环状二核苷酸:2'-O/3'-O键、硫代磷酸酯键、腺嘌呤和/或鸟嘌呤类似物和/或2'-OH修饰(例如,用甲基保护2'-OH或用-F或-N3替代2'-OH)。在一些实施方案中,一种或多种STING激动剂选自BMS-986301、MK-1454、ADU-S100、diABZI、3’3’-cGAMP和/或2’3’-cGAMP。
在一些实施方案中,一种或多种癌症疫苗选自HPV疫苗、乙型肝炎疫苗、奥克非格(Oncophage)和/或普洛韦格(Provenge)。
在一些实施方案中,一种或多种免疫调节剂可包含免疫检查点抑制剂。免疫检查点抑制剂可靶向免疫检查点受体或包含例如以下的受体的组合:CTLA-4、PD-1、PD-L1、PD-L2、T细胞免疫球蛋白和粘蛋白3(TIM3或HAVCR2)、半乳糖凝集素9、磷脂酰丝氨酸、淋巴细胞活化基因3蛋白质(LAG3)、I类MHC、II类MHC、4-1BB、4-1BBL、OX40、OX40L、GITR、GITRL、CD27、CD70、TNFRSF25、TL1A、CD40、CD40L、HVEM、LIGHT、BTLA、CD160、CD80、CD244、CD48、ICOS、ICOSL、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2、TMIGD2、嗜乳脂蛋白(butyrophilin)(包括BTNL2)、Siglec家族成员、TIGIT、PVR、杀伤细胞免疫球蛋白样受体、ILT、白细胞免疫球蛋白样受体、NKG2D、NKG2A、MICA、MICB、CD28、CD86、SIRPA、CD47、VEGF、神经纤毛蛋白(neuropilin)、CD30、CD39、CD73、CXCR4和/或CXCL12。
在一些实施方案中,免疫检查点抑制剂选自乌瑞鲁单抗、PF-05082566、MEDI6469、TRX518、瓦力单抗(varlilumab)、CP-870893、派姆单抗(PD1)、纳武单抗(PD1)、阿特珠单抗(以前为MPDL3280A)(PD-L1)、MEDI4736(PD-L1)、阿维鲁单抗(PD-L1)、PDR001(PD1)、BMS-986016、MGA271、利瑞鲁单抗、IPH2201、埃玛图单抗(emactuzumab)、INCB024360、伽伦替布(galunisertib)、尤洛库单抗(ulocuplumab)、BKT140、巴维昔单抗(bavituximab)、CC-90002、贝伐珠单抗和/或MNRP1685A。
在一些实施方案中,一种或多种免疫调节剂可包含补体路径调节剂。补体路径调节剂调节补体活化路径。补体路径调节剂可用以阻断C3和/或C3a和/或C3aR1受体的作用,或可用以阻断C5和/或C5a和/或C5aR1受体的作用。在一些实施方案中,补体路径调节剂为C5补体路径调节剂且可选自依库珠单抗、拉夫珠单抗(ravulizumab)(ALXN1210)、ABP959、RA101495、特度鲁单抗(tesidolumab)(LFG316)、奇穆拉(zimura)、可伐利单抗(crovalimab)(RO7112689)、帕泽利单抗(pozelimab)(REGN3918)、GNR-045、SOBI005和/或康复素(coversin)。在一些实施方案中,补体路径调节剂为C5a补体路径调节剂且可选自塞姆迪司兰(cemdisiran)(ALN-CC5)、IFX-1、IFX-2、IFX-3和/或奥伦达利珠单抗(olendalizumab)(ALXN1007)。在一些实施方案中,补体路径调节剂为C5aR1补体路径调节剂且可选自ALS-205、MOR-210/TJ210、DF2593A、DF3016A、DF2593A、阿伐可泮(avacopan)(CCX168)和/或IPH5401。
在一些实施方案中,一种或多种免疫调节剂可包含抗TNFα剂。在一些实施方案中,抗TNFα剂可为抗体或其抗原结合片段、融合蛋白、可溶性TNFα受体(例如,可溶性TNFR1或可溶性TNFR2)、抑制性核酸或小分子TNFα拮抗剂。在一些实施方案中,抑制性核酸可为核糖核酸酶、小发夹RNA、小干扰RNA、反义核酸或适体。在一些实施方案中,抗TNFα剂选自阿达木单抗、聚乙二醇赛妥珠单抗、依那西普(etanercept)、戈利木单抗、英利昔单抗、CDP571和其生物类似物(例如,阿达木单抗-adbm(adalimumab-adbm)、阿达木单抗-adaz(adalimumab-adaz)、阿达木单抗-atto(adalimumab-atto)、依那西普-szzs(etanercept-szzs)、英利昔单抗-abda(infliximab-abda)和英利昔单抗-dyyb(infliximab-dyyb))。
在一些实施方案中,一种或多种免疫调节剂可包含阿奇霉素(azithromycin)、克拉霉素(clarithromycin)、红霉素(erythromycin)、左氧氟沙星(levofloxacin)和/或罗红霉素(roxithromycin)。
在一些实施方案中,一种或多种抗生素选自阿米卡星(amikacin)、庆大霉素(gentamicin)、卡那霉素(kanamycin)、新霉素(neomycin)、奈替米星(netilmicin)、妥布霉素(tobramycin)、巴龙霉素(paromomycin)、链霉素(streptomycin)、大观霉素(spectinomycin)、格尔德霉素(geldanamycin)、除莠霉素(herbimycin)、利福昔明(rifaximin)、氯碳头孢(loracarbef)、厄他培南(ertapenem)、多尼培南(doripenem)、亚胺培南(imipenem)、西司他汀(cilastatin)、美罗培南(meropenem)、头孢羟氨苄(cefadroxil)、头孢唑林(cefazolin)、头孢噻吩(cefalotin)、头孢噻啶(cefalothin)、头孢氨苄(cefalexin)、头孢克洛(cefaclor)、头孢孟多(cefamandole)、头孢西丁(cefoxitin)、头孢丙烯(cefprozil)、头孢呋辛(cefuroxime)、头孢克肟(cefixime)、头孢地尼(cefdinir)、头孢托仑(cefditoren)、头孢哌酮(cefoperazone)、头孢噻肟(cefotaxime)、头孢泊肟(cefpodoxime)、头孢他啶(ceftazidime)、头孢布烯(ceftibuten)、头孢唑肟(ceftizoxime)、头孢曲松(ceftriaxone)、头孢吡肟(cefepime)、头孢洛林酯(ceftaroline fosamil)、头孢吡普(ceftobiprole)、替考拉宁(teicoplanin)、万古霉素(vancomycin)、特拉万星(telavancin)、达巴万星(dalbavancin)、奥利万星(oritavancin)、克林霉素(clindamycin)、林可霉素(lincomycin)、达托霉素(daptomycin)、阿奇霉素、克拉霉素、地红霉素、红霉素、罗红霉素、醋竹桃霉素(troleandomycin)、泰利霉素(telithromycin)、螺旋霉素(spiramycin)、氨曲南(aztreonam)、呋喃唑酮(furazolidone)、呋喃妥因(nitrofurantoin)、利奈唑胺(linezolid)、泊斯唑胺(posizolid)、雷德唑胺(radezolid)、甲苯咪唑(torezolid)、阿莫西林(amoxicillin)、氨苄西林(ampicillin)、阿洛西林(azlocillin)、羧苄西林(carbenicillin)、氯唑西林(cloxacillin)、双氯西林(dicloxacillin)、氟氯西林(flucloxacillin)、美洛西林(mezlocillin)、甲氧西林(methicillin)、萘夫西林(nafcillin)、苯唑西林(oxacillin)、青霉素G、青霉素V、哌拉西林(piperacillin)、替莫西林(temocillin)、替卡西林(ticarcillin)、克拉维酸(calvulanate)、氨苄西林、舒巴坦(subbactam)、三唑巴坦(tazobactam)、替卡西林(ticarcillin)、棒酸盐(clavulanate)、杆菌肽(bacitracin)、粘菌素(colistin)、多粘菌素(polymyxin)B、环丙沙星(ciprofloxacin)、依诺沙星(enoxacin)、加替沙星(gatifloxacin)、吉米沙星(gemifloxacin)、左氧氟沙星、洛美沙星(lomefloxacin)、莫西沙星(moxifloxacin)、萘啶酸(nalidixic acid)、诺氟沙星(norfloxacin)、氧氟沙星(ofloxacin)、曲伐沙星(trovafloxacin)、格帕沙星(grepafloxacin)、司帕沙星(sparfloxacin)、替马沙星(temafloxacin)、磺胺米隆(mafenide)、磺胺醋酰胺(sulfacetamide)、磺胺嘧啶(sulfadiazine)、磺胺嘧啶银、磺胺地托辛(sulfadimethoxine)、磺胺甲基异恶唑(sulfamethoxazole)、胺苯磺胺(sulfanamide)、柳氮磺胺吡啶(sulfasalazine)、磺胺异恶唑(sulfisoxazole)、甲氧苄啶-磺胺甲基异恶唑(trimethoprim-sulfamethoxazole)、磺胺类花青素(sulfonamideochrysoidine)、地美环素(demeclocycline)、米诺环素(minocycline)、土霉素(oytetracycline)、四环素(tetracycline)、氯苯吩嗪(clofazimine)、氨苯砜(dapsone)、达普瑞霉素(dapreomycin)、环丝氨酸(cycloserine)、乙胺丁醇、乙硫异烟胺、异烟肼、吡嗪酰胺(pyrazinamide)、利福平(rifampicin)、利福布汀(rifabutin)、利福喷丁(rifapentine)、链霉素、胂凡纳明(arsphenamine)、氯胺苯醇(chloramphenicol)、磷霉素(fosfomycin)、梭链孢酸(fusidic acid)、甲硝哒唑(metronidazole)、莫匹罗星(mupirocin)、平板霉素(platensimycin)、喹奴普丁(quinupristin)、达勒普丁(dalopristin)、甲砜霉素(thiamphenicol)、替加环素(tigecycyline)、替硝唑(tinidazole)、甲氧苄啶(trimethoprim)和/或泰斯巴汀(teixobactin)。
在一些实施方案中,一种或多种抗生素可包含一种或多种细胞毒性抗生素。在一些实施方案中,一种或多种细胞毒性抗生素选自放线菌素(actinomycin)、蒽醌(anthracenedione)、蒽环霉素(anthracycline)、沙立度胺、二氯乙酸、烟酸、2-脱氧葡萄糖和/或氯法齐明(chlofazimine)。在一些实施方案中,一种或多种放射菌素选自放线菌素D、杆菌肽、粘菌素(多粘菌素E)和/或多粘菌素B。在一些实施方案中,一种或多种蒽醌选自米托蒽醌和/或派蒽醌(pixantrone)。在一些实施方案中,一种或多种蒽环霉素选自博莱霉素、小红莓(阿德力霉素)、道诺霉素(柔红霉素(daunomycin))、表柔比星(epirubicin)、艾达霉素、丝裂霉素、普卡霉素(plicamycin)和/或戊柔比星(valrubicin)。
在一些实施方案中,一种或多种抗真菌剂选自联苯苄唑(bifonazole)、布康唑(butoconazole)、克霉唑(clotrimazole)、益康唑(econazole)、酮康唑(ketoconazole)、卢立康唑(luliconazole)、咪康唑(miconazole)、奥莫康唑(omoconazole)、奥昔康唑(oxiconazole)、舍他康唑(sertaconazole)、硫康唑(sulconazole)、噻康唑(tioconazole)、阿巴康唑(albaconazole)、艾菲康唑(efinaconazole)、依普康唑(epoziconazole)、氟康唑(fluconazole)、艾沙康唑(isavuconazole)、伊曲康唑(itraconazole)、泊沙康唑(posaconazole)、丙环唑(propiconazole)、里氟康唑(ravusconazole)、特康唑(terconazole)、伏立康唑(voriconazole)、阿巴芬净(abafungin)、阿莫罗芬(amorolfin)、布替萘芬(butenafine)、萘替芬(naftifine)、特比萘芬(terbinafine)、阿尼芬净(anidulafungin)、卡泊芬净(caspofungin)、米卡芬净(micafungin)、苯甲酸、环吡酮、氟胞嘧啶、5-氟胞嘧啶、灰黄霉素(griseofulvin)、卤普罗近(haloprogin)、托萘酯(tolnaflate)、十一碳烯酸和/或秘鲁香脂(balsam of Peru)。
在一些实施方案中,一种或多种抗蠕虫剂选自苯并咪唑类(包括阿苯达唑(albendazole)、甲苯达唑(mebendazole)、噻苯达唑(thiabendazole)、芬苯达唑(fenbendazole)、三氯苯达唑(triclabendazole)和氟苯达唑(flubendazole))、阿维菌素(abamectin)、二乙碳酰嗪(diethylcarbamazine)、伊维菌素(ivermectin)、苏拉明(suramin)、双羟萘酸噻嘧啶(pyrantel pamoate)、左旋咪唑(levamisole)、水杨酰苯胺类(包括氯硝柳胺(niclosamide)和氯羟柳胺(oxyclozanide))和/或硝唑尼特(nitazoxanide)。
在一些实施方案中,其它活性剂选自生长抑制剂;抗炎剂(包括非类固醇抗炎剂;小分子抗炎剂(例如秋水仙碱(colchicine));和靶向例如TNF、IL-5、IL-6、IL-17或IL-33的抗炎生物制剂);JAK抑制剂;磷酸二酯酶抑制剂;CAR T疗法;抗牛皮癣剂(包括蒽三酚(anthralin)和其衍生物);维生素和维生素衍生物(包括类视黄素和VDR受体配体);类固醇;皮质类固醇;糖皮质激素(例如地塞米松(dexamethasone)、泼尼松(prednisone)和曲安奈德(triamcinolone acetonide));离子通道阻断剂(包括钾通道阻断剂);免疫系统调控剂(包括环孢素(cyclosporin)、FK 506和糖皮质激素);促黄体生成素释放激素激动剂(例如亮丙瑞林(leuprolidine)、戈舍瑞林(goserelin)、曲普瑞林(triptorelin)、组氨瑞林(histrelin)、比卡鲁胺、氟他胺和/或尼鲁米特);激素(包括雌激素);和/或尿酸降低剂(例如别嘌呤醇(allopurinol))。
除非另外陈述,否则在本发明的第九到第十七方面中的任一个中,受试者可以是任何人类或其它动物。通常,受试者为哺乳动物,更通常为人类或家养哺乳动物,例如牛、猪、羔羊、绵羊、山羊、马、猫、狗、兔、小鼠等。最通常,受试者为人类。
本发明中所用的药剂中的任一种可通过经口、肠胃外(包括静脉内、皮下、肌肉内、皮内、气管内、腹膜内、关节内、颅内和硬膜外)、气管(气雾剂)、经直肠、经阴道、眼部或局部(包括经皮、经颊、经粘膜、舌下和局部经眼)施用来施用。
通常,所选择的施用模式为最适合于所治疗或预防的病症、疾病或疾患的施用模式。在施用一种或多种其它活性剂的情况下,施用模式可与施用本发明的化合物、盐、溶剂合物、前药或药物组合物的模式相同或不同。
当然,本发明的化合物、盐、溶剂合物或前药的剂量将随所治疗或预防的疾病、病症或疾患而变化。一般来说,合适的剂量将在每天每千克接受者体重的0.01到500mg的范围内。所要剂量可以适当时间间隔,例如每隔一天一次、一天一次、一天两次、一天三次或一天四次提供。所要剂量可以单位剂型例如每单位剂型含有1mg到50g活性成分施用。
为了避免疑义,在可行的情况下,本发明的给定方面的任何实施方案可与本发明的相同方面的任何其它实施方案组合出现。另外,在可行的情况下,应理解,本发明的任何方面的任何优选的、典型的或任选的实施方案也应视为本发明的任何其它方面的优选的、典型的或任选的实施方案。
附图说明
现将仅借助于实施例参照附图来描述本发明的实施方案,在所述附图中:
图1:MCC7840、MCC950 IZ1201和IZ1438的结构和其在含光解溶液的甲醇中的光产物;
图2:显示在存在或不存在过量MCC950或MCC7840的情况下用光探针IZ1201或IZ1438光标记的hNLRP3的凝胶内荧光扫描;
图3:在对应于hNLRP3的凝胶带中鉴定的蛋白质的等级次序分布;
图4:在用与MCC7840竞争的IZ1438进行重组hNLRP3标记之后完整的和IZ1438修饰的hNLRP3肽195TCESPVSPIK204的MS1强度值;
图5:hNLRP3的完整或IZ1438修饰的肽TCESPVSPIK的MS2光谱;
图6:确认在过表达HEK细胞的上清液(A)中和在管柱洗脱级分(B)中存在NLRP3;
图7:使用两种不同抗体确认在过表达HEK细胞的上清液中存在NLRP3和在对照未转染的HEK细胞中不存在NLRP3(A及B);
图8:放射性配体结合分析优化;
图9:放射性配体结合研究中的组织线性;
图10:放射性配体结合研究,使用未转染HEK裂解物进行背景评估;
图11:结合饱和研究;
图12:放射性配体结合的ATP竞争;
图13:具有预测的配体结合位点的NLRP3模型;
图14:预测最可能的配体结合位点,与NLRC4和NOD2结构两者的ADP的X射线晶体学结构重叠的NLRP3模型;
图15:MCC950模型化至活性位点中的NLRP3模型,其中磺酰脲基位于Walker A基序与His522残基之间;
图16:选择与隐热蛋白相关周期性综合征(CAPS)相关的突变的NLRP3模型,所述突变被鉴定为接近于结合位点。
实施例
实施例1:光亲和性标记质谱(PALMS)
总结
本研究的目的是应用光亲和性标记质谱(PALMS)来验证MCC7840与人类NLRP3(hNLRP3)的相互作用且鉴定有助于hNLRP3的MCC7840结合位点的氨基酸残基。
如所属领域的技术人员将知道,PALMS使用携带光反应性官能团和报道子官能团的生物活性配体的类似物(光亲和性探针)。基于母体分子的结构-活性关系来设计和合成光亲和性探针。重要的是,与非衍生配体相比,建立所并入的光反应性官能团和报道子官能团不会显著改变配体与其受体的结合亲和性和其功能性。在PALMS期间,将光亲和性探针与重组蛋白质靶标一起孵育,并且用UV光照射。在复合物形成之后,光反应性基团的UV照射产生将光亲和性探针共价交联到其大分子结合配偶体的高反应性化学物质(例如,碳烯、氮烯或自由基)。光交联的蛋白质靶标可以通过点击化学用荧光或表位标签(例如,TAMRA、生物素)来标记,并且随后通过报道基团使用SDS-PAGE和凝胶内荧光扫描或蛋白质印迹可视化。探针与蛋白质配偶体之间的共价键形成使得能够使用LC-MS/MS进行结合口袋中的探针修饰的肽和氨基酸的后续鉴定。可以通过在对照样品中添加竞争物来监测光亲和性标记事件的功能选择性。
研究设计
在第一步骤中,优化了使用两个光敏探针进行重组hNLRP3的光标记的实验条件。在第二步骤中,使用两个光敏探针中的一个和由无标记定量LC-MS/MS分析鉴定的光标记肽/氨基酸来进行hNLRP3的光标记。
方法
通过基于MCC7840的SAR来设计和合成MCC7840的光活化类似物。选择两个保留母体分子MCC7840的生物标志光探针IZ1201和IZ1438(在细胞IL-1β释放分析中评估)以对Sf21细胞中产生的纯化的重组hNLRP3(6His-SUMO-TEV-NLRP3[125-1036])执行光亲和性标记实验。为确保有效光标记hNLRP3,选择优化条件以进行进一步PAL-MS实验:在存在或不存在过量母体药物MCC7840 50μM的情况下,用25μM IZ1438进行30min处理。在蛋白质消化之后,通过无标记定量质谱分析(MS)分析探针标记的肽。用MaxQuant软件分析质量偏移为438.1727m/z的肽加合物,随后人工判读CID片段光谱。
结果
■在如THP-1细胞中的IL-1β释放分析中所示的细胞条件下,相较于母体化合物,探针中的最低双官能光交联剂对靶标接合几乎没有负面影响。
■IZ1201和IZ1438为可推断活细胞中的MCC7840-靶标相互作用的细胞可渗透探针。
■在365nm处的UV照射后,IZ1201和IZ1438产生碳烯中间物,其随后重排成乙烯产物,或与溶剂分子反应以与甲醇或酮产物形成高度稳定的C-O共价键。
■IZ1201和IZ1438结合至重组hNLRP3并且它们的结合由母体化合物MCC7840以及NLRP3特定抑制剂MCC950抑制。
■在MS1分析期间,鉴定出一种经修饰的肽195TCESPVSPIK204,其特征质量偏移为+438,1727m/z,对应于IZ1438分子量减去N2。
■探针修饰的肽未在对照样品中检测出,到且在存在MCC7840的情况下丰度较低(因此与IZ1438竞争)。
■在MS2分析期间,鉴定出特征质量偏移为+265,0582m/z的经修饰的肽,这是由在CID片段化后连接到肽的探针的裂解造成的。
■探针修饰的肽和其完整对应物的MS2分析将265.0582m/z的加合物的位点定位于E197。
结论(总结)
这些结果表明,IZ1438以MCC7840竞争性方式在hNLRP3中光标记E197。
详细说明
PALMS使用携带光反应性官能团和报道子官能团的光亲和性探针(生物活性配体(小分子、肽)的类似物)。基于母体分子的结构-活性关系来设计和合成光亲和性探针。重要的是,与非衍生配体相比,建立所并入的光反应性官能团和报道子官能团不会显著改变配体与其受体的结合亲和性和其功能性。在PALMS期间,将光亲和性探针与重组蛋白质靶标一起孵育,并且用UV光照射。在复合物形成之后,光反应性基团的UV照射产生将光亲和性探针共价交联到其大分子结合配偶体的高反应性化学物质(例如,碳烯、氮烯或自由基)。光交联的蛋白质靶标可以通过点击化学用荧光或表位标签(例如,TAMRA、生物素)来标记,并且随后通过报道基团使用SDS-PAGE和凝胶内荧光扫描或蛋白质印迹可视化。探针与蛋白质配偶体之间的共价键形成使得能够使用LC-MS/MS进行结合口袋中的探针修饰的肽和氨基酸的后续鉴定。可以通过在对照样品中添加竞争物来监测光亲和性标记事件的功能选择性。
材料和方法
材料
将Sf21昆虫细胞系中产生的重组hNLRP3[6His-SUMO-TEV-NLRP3(125-1036),分子量116,929Da]在10mM Tris-HCl(pH 8.0)、150mM NaCl、1mM DTT中存储于-80℃下,直至使用。在研究中使用两种不同批次:批次1(0.46mg/mL;4μM)和批次2(0.20mg/mL;2μM)。光探针IZ1201和IZ1438以及母体化合物MCC950和MCC7840由Inflazome提供(表A)。
表A:MCC7840和MCC950以及两种类似物IZ1201和IZ1438的特征。
重组人类NLRP3的光亲和性标记
将重组人类NLRP3(4μg批次1或批次2,3.4pmol,最终浓度0.68μM)单独孵育于96孔板(最终反应体积,50μL)中的呈指定浓度(从DMSO储备液稀释,由此DMSO在最终溶液中未超出1%)的具有光探针(IZ1201或IZ1438)中的每一者的磷酸盐缓冲盐水(PBS)或DMSO中。在室温下于黑暗中孵育30min之后,将混合物在4℃下用365nm处的UV光光照射20min。对于竞争性光亲和性标记实验,用呈指定浓度的母体化合物MCC950或MCC7840进行15min预处理之后进行光探针处理和光解。在UV照射之后,添加1%SDS和10mM DTT,并且在56℃下孵育1h之后,将蛋白质样品在室温下于黑暗中用30mM碘乙酰胺处理45min。探针标记的hNLRP3是通过铜点击化学,使用Click-iTTM蛋白质反应缓冲液试剂盒(ThermoFisher Scientific)根据制造商的说明书用四甲基罗丹明(TAMRA)叠氮化物(来自1mM储备溶液的100μM TAMRA叠氮化物)标记。添加预冷却到-20℃的干燥丙酮(9体积),且将混浊混合物充分地涡旋且在-20℃下孵育过夜。在离心(15,000×g,10分钟,4℃)之后,将上清液倒掉并且用-20℃丙酮洗涤剩余的球粒。通过离心去除洗涤上清液且将所沉淀蛋白质球粒在室温下风干10min。
交联蛋白质的基于凝胶的分析
将在存在或不存在过量母体化合物MCC950或MCC7840的情况下预先用IZ1201或IZ1438光标记的hNLRP3(4μg,3.4pmol)的干燥球粒再悬浮于50μL SDS负载缓冲液(含有2.5%v/v 2-巯基乙醇的Bio Rad的XT样品缓冲液)中且加热(60℃,30min)。使用SDS-PAGE(4-15%CriterionTM TGX Stain-FreeTM蛋白质凝胶,Bio Rad)解析蛋白质且通过凝胶内荧光扫描使用具有绿色LED光作为激发源和BP600/20nm发射滤光片的ChemiDocTM MP成像系统(Bio Rad)来分析。在凝胶内荧光扫描之后,凝胶用考马斯蓝染色以确保相同量的蛋白质样品负载于每个泳道中且用ChemiDocTM MP成像系统成像。通过使用ImageJ 1.52e测量对应凝胶带的荧光强度且针对用考马斯蓝染色的hNLRP3凝胶带的强度值将这个值标准化以控制负载差异来定量评估hNLRP3中每个光探针的光并入。
制备经标记hNLRP3以进行MS分析
将含重组hNLRP3(55μg批次2,47pmol,最终浓度0.94μM)的50μL磷酸盐缓冲盐水(PBS)与50μM MCC7840或媒介物一起预孵育15min,且接着在室温下用25μM IZ1438处理另外30min。在用SDS负载缓冲液(4X储备液,17μL)淬灭光交联反应之前,将样品在4℃下光照射20min。使用SDS-PAGE(4-15%CriterionTM TGX Stain-FreeTM蛋白质凝胶,Bio Rad)解析蛋白质,且将凝胶用考马斯蓝染色。从凝胶切除对应于hNLRP3的蛋白质带,并且在37℃下用250μl 50mM NH4HCO3和乙腈(ACN)(1:1)洗涤2h,直至去除考马斯蓝。此后,将凝胶片在56℃下用含10mM DTT的50mM NH4HCO3处理30min,并且用50mM NH4HCO3和ACN(1:1)洗涤两次。这之后为在室温下用含55mM碘乙酰胺的50mM NH4HCO3处理35min,用50mM NH4HCO3和ACN(1:1)洗涤两次,在SpeedVac浓缩器中干燥且在含有3μg胰蛋白酶/Lys-C混合物(质谱级)(Promega)的60μL 50mM NH4HCO3溶液中复水。将上述混合物在黑暗中在平缓搅拌下在37℃下孵育过夜以进行消化。在消化之后,进行10min的短暂旋转,并且将“胰蛋白酶/Lys-C级分”收集于新制AxygenTM MaxyClear Snaplock微管(ThemoFisher Scientific)中。凝胶片用100μL 0.2%甲酸和ACN(1:1)再萃取两次,且在频繁涡旋下用50μL乙醇和ACN(1:1)再萃取一次,持续15min。将上清液与“胰蛋白酶/Lys-C级分”组合在一起,使用SpeedVac浓缩器浓缩到干燥。将肽(最终浓度0.55μg/μL)在100μL含0.2%甲酸和0.3%ACN的水中复原且存储于-20℃下直至通过LC-MS/MS进行分析为止。
肽混合物的质谱分析
通过nanoLC-MS/MS,使用耦合到配备有纳米电喷雾源的QExactive HF质谱仪(Thermo Scientific)的nanoAcquity UPLC(Waters)分析肽混合物。将样品在含0.2%甲酸和0.3%ACN的水中稀释到0.05μg/μl的最终浓度。将样品(1μg,20μL)在含0.2%甲酸和0.3%ACN的水中以20μl/min负载到C18前置柱(Symmetry C18 NanoAcquity,5μm,180μm×20mm)上。在脱盐步骤(3min)之后,将前置柱与在92%溶剂A(0.2%甲酸于水中)和8%溶剂B(0.2%甲酸和90%ACN于水中)中平衡的分析型BEH C18管柱(130μm;1.7μm,75μM×250mm,Waters)在线切换。XCalibur软件控制MS和色谱功能。在165min期间以270nL/min流动速率使用8-35%梯度的溶剂B洗脱肽。质谱仪以数据依赖性采集模式操作以在MS与MS/MS采集之间自动切换。在m/z 200下以60,000的分辨率采集调查全扫描MS光谱(m/z 325-1300)。将AGC设定为3×106,其中最大注入时间为45ms。靶向前20个最强的离子以供通过标准化碰撞能量为26%(对于3.3×104的强度阈值,AGC为1×105且最大注射时间为60ms)的高量碰撞解离(HCD)进行片段化。将动态排除时间窗口设定为30s以防止重复选择相同的肽。以谱型记录MS/MS光谱,其中分辨率为15,000。
MS数据处理
用MaxQuant软件(版本1.5.3.8)处理原始文件(1)以进行肽和蛋白质鉴定和定量。使用Andromeda搜索引擎针对含有人类NLRP3截断序列(125-1036)的串接数据库和草地贪夜蛾(Sf21)数据库,使用以下参数搜索胰蛋白酶消化物的MS/MS原始文件:将半胱氨酸的胺甲酰胺基甲基化设定为固定修饰,而将N端乙酰化和甲硫氨酸氧化设定为可变的修饰。所有肽需要具有五个氨基酸的最小肽长度和最多两个遗失裂解(miss cleavage)。需要胰蛋白酶裂解的严格特异性,从而使得N端裂解为脯氨酸。在MS和MS/MS中将质量容差分别设定为4.5ppm和20ppm。对如先前所描述具有蛋白质序列的修饰反向的串接靶标诱饵数据库进行搜索(2)。将蛋白质和肽鉴定的错误发现率(FDR)设定为最大1%。为了在不同运行中验证和传送鉴定,启用了MaxQuant中的‘运行间匹配(match between runs)’选项,其中匹配时间窗口为0.7min且比对时间窗口为20min。通过实施于标准搜索中的MaxQuant中的“依赖性肽”设置来鉴定未知的修饰。所实施的算法以无偏方式执行光谱匹配以鉴定经修饰的肽。如果未鉴定的光谱匹配所鉴定的光谱,那么将报道理论和所观测的前体质量与所匹配序列的质量偏移(对应于肽的修饰)。如果经修饰的肽来源于FDR为1%且质量容差为6.5mDa的已鉴定的未经修饰的肽,那么将仅鉴定出经修饰的肽。从allPeptides.txt以及碱基与依赖性肽之间的ΔM质量偏移提取经修饰的肽。将所有氨基酸视为用于修饰的可能残基。用于搜索探针修饰的肽的修饰质量对于IZ1438为+438.17256m/z,其为对应探针减去分子氮的质量。将这种修饰设定为所有MaxQuant检索中的可变修饰。出于定量目的,使用由MaxQuant计算的无标记定量(LFQ)强度。LFQ度量通过MaxLFQ算法从原始强度中推导出,所述MaxLFQ算法使用特定标准化程序以及特定聚集方法,通过考虑每种蛋白质在不同定量样品的所有成对比较中测量的所有肽比率来计算蛋白质强度(3)。对于LFQ定量,考虑仅由至少两种独特肽比率(最小LFQ比率计数=2)计算的蛋白质比率用于计算LFQ蛋白质强度。人工地进行MaxQuant处理数据的分析。简单来说,对于“依赖性肽”分析,将“all.peptides.txt”文件在Excel中打开且针对DP蛋白质“sp|NRLP3-EV6347|”、DP质量差“400<X<460”和DP得分“>60”进行筛选。将DP质量偏移为+438.17256m/z(具有5ppm的容差)且仅存在于两种条件“NLRP3+IZ1438”和“NLRP3+IZ1438+MCC7840”中而不存在于对照“NRLP3”中的所选肽被视为阳性命中(positive hits)。人工地进行阳性命中的验证。用Xcalibur软件观测MS光谱以检查未经修饰和经修饰的肽的存在。理想地,应在所有三种条件下检测未经修饰的肽,而应在条件“NLRP3+IZ1438”中和在较小程度上在条件“NLRP3+IZ1438+MCC7840”而非对照“NLRP3”中检测到用+438.17265m/z光加合物修饰的肽。使用MaxQuant的查看器程序观测MS/MS光谱以标注未经修饰的肽的y和b离子。通过Xcalibur软件打开所关注的未经修饰和经修饰的肽的MS/MS光谱(分别为DP碱基扫描和DP修改扫描),且比较两种肽的序列以确定序列中光加合物的位置。预期在y和/或b离子上的偏移为+438.17265m/z(具有5ppm的容差)。
甲醇中光解产物的LC-MS/MS分析
通过使用LC-MS/MS分析所产生的光产物来单独地检查甲醇中双吖丙啶探针IZ1201和IZ1438的光解。在4℃下将光探针(70pmol/μL于MeOH中)保持在黑暗中或在365nm下光照射20min且随后在含0.05%三氟乙酸(TFA)和0.2%ACN的水中稀释140倍,达到500fmol/μL的最终浓度。通过nanoLC/MS-MS,使用耦合到配备有纳米电喷雾源的OrbitrapVelos Elite(Thermo Fisher Scientific)的Ultimate 3500RSLC系统(Dionex)分析光探针溶液。将二十微升稀释的光探针溶液(10pmol)在含0.05%TFA和2%ACN的水中以20μl/min负载到C-18前置柱(Acclaim Pep Map C18,5μm,300μm×5mm)上。在脱盐步骤(3min)之后,将前置柱与在97%溶剂A(0.2%甲酸)和3%溶剂B(0.2%甲酸和80%ACN于水中)中平衡的分析型BEH C18管柱(130μm;1.7μm,75μM×250mm,Waters)在线切换。将探针通过3-99%梯度的溶剂B在13min期间以0.250nl/min的流动速率使用纳米HPLC系统(U3000,Thermo Fisher Scientific)洗脱且通过纳米电喷雾离子源直接电喷射到Orbitrap VelosElite中。XCalibur软件控制MS和色谱功能。质谱仪以数据依赖性采集模式操作以在MS与MS/MS采集之间自动切换。以120,000的分辨率采集调查全扫描MS光谱(m/z 100-1,600)。将AGC设定为1×106,其中最大注入时间为200ms。靶向前7个最强的离子以供通过标准化碰撞能量为28%(AGC为1×105)和最大注入时间为10ms的碰撞诱导的解离(CID)进行片段化。分离窗口在2m/z下。将动态排除时间窗口设定为60s以防止重复选择相同的肽。由每种物质测量的MS离子强度(或峰面积)定量在光解前和光解后观测到的不同物质的相对丰度。基于MS离子强度值计算混合物中每种组分的组成百分比。
结果
通过Inflazome设计且合成含有光反应性交联和分选功能性两者的MCC7840的两种光活化类似物:图1:MCC7840和MCC950、IZ1201和IZ1438的结构和其在含光解溶液的甲醇中的光产物。相较于光解前的探针,在LC-MS模式中观测到的分子离子的(A)结构,(B)质量、分子式和分子质量偏移。由每种物质测量的MS离子强度定量在光解前和光解后观测到的不同物质的相对丰度。基于MS离子强度值计算混合物中每种组分的组成百分比。
由于脂肪族双吖丙啶部分的小尺寸(以最小化对蛋白质结合的干扰)和在光解后产生高反应性碳烯中间物所需的较短照射时间,将脂肪族双吖丙啶部分选择为光交联基团。我们使用小脂肪族炔烃报道基团,其可使用公认的生物正交点击化学共轭到合适的报道子标签(荧光或生物素叠氮化物基团)以用于通过LC-MS/MS进行的后续离体PD/靶标鉴定或探针靶标复合物的动态细胞成像。将先前由Li等人2013(4)描述的含最少末端炔烃双吖丙啶光交联剂极为接近地并入到药效团,从而最大化在形成高反应性碳烯时光反应性部分优先与结合配偶体而不与溶剂反应的可能性。
为进行PALMS实验,有必要选择保留母体分子MCC7840的生物标志且具有类似于MCC7840的作用模式和胞内分子相互作用的MCC7840的光活化类似物。在这个目的中,在THP-1细胞中的IL-1β释放分析中评估MCC7840、MCC950和两个光探针IZ1201和IZ1438的效力(IC50值)和抑制性作用。
炎性体用以活化胱天蛋白酶1,其接着负责以蛋白分解方式裂解和活化促炎性细胞因子白介素-1β(IL-1β)和IL-18。炎性体通过引发细胞焦亡(促炎性细胞死亡的形式)进一步促进炎症。THP-1细胞中的IL-1β释放分析用于评估不同分子抑制炎性体介导的细胞因子分泌的能力。
如表B中所示,MCC950为所测试的四种化合物当中的最有效化合物,而MCC7840和光探针IZ1438彼此具有相当的IC50值,比MCC950小4到6倍。光探针IZ1201的活性比IZ1438弱约6倍。
这些结果指示,在细胞条件下,相较于母体化合物,探针中的最低双官能光交联剂对靶标接合具有最小到几乎无负面影响。
表B:MCC7840、MCC950和光活化类似物IZ1201和IZ1438在用LPS和尼日利亚菌素(nigericin)刺激之后抑制IL-1β从THP-1细胞释放的IC50值。
重组人类NLRP3的光亲和性标记和凝胶内荧光分析
为验证光探针与hNLRP3之间的直接相互作用,我们进行体外光亲和性标记实验。简单来说,将来自批料1或批料2的重组hNLRP3用浓度增加的IZ1201或IZ1438处理30min,随后进行UV照射,以引发光交联。随后,通过具有红色荧光TAMRA叠氮化物染料的探针上的脂肪族炔烃官能团使探测标记的蛋白质经历点击反应,使得探测标记的蛋白质选择性地用TAMRA报道子荧光团标记。蛋白质接着通过SDS-PAGE解析,随后进行凝胶内荧光扫描,以使荧光蛋白可视化。
图2:显示在不存在或存在过量MCC950或MCC7840的情况下用IZ1201或IZ1438光标记的hNLRP3的凝胶内荧光扫描。
将hNLRP3用媒介物或指定浓度的IZ1201或IZ1438标记1h,随后进行标准光亲和性标记(PAL)程序。在光解之后,使探针修饰的蛋白质与TAMRA-叠氮化物标签发生点击反应并且通过SDS-PAGE和凝胶内荧光扫描进行分析。对于竞争PAL实验,将来自批次1(B)或批次2(C)的hNLRP3与MCC7840或MCC950(25或50μM)或媒介物预孵育15min,随后与或不与IZ1201或IZ1438(1μM)一起孵育1h,且这之后为如上文所描述的UV照射、与TAMRA-叠氮化物标签的点击反应和凝胶内荧光扫描。通过测量对应凝胶带的荧光强度(黑色箭头)且相对于用考马斯蓝染色的hNLRP3凝胶带的强度值将这个值标准化来定量评估hNLRP3中每个光探针的光并入。
如图2A中所示,用两种探针和针对两个hNLRP3批次观测到类似的标记模式。我们观测到两种探针剂量依赖性光并入到hNLRP3(117kDa)中。对于两种探针,光并入的产率类似。似乎也标记其它蛋白质带(~28、~60、~90和~300kDa),但标记程度比hNLRP3低得多。用1μM的IZ1201或IZ1438处理提供了足够的体外hNLRP3标记以设想使用浓度增加的母体化合物MCC950和MCC7840进行的竞争实验。
为了探究对hNLRP3的IZ1201或IZ1438标记的特异性,进行了一组使用MCC950和MCC7840进行的竞争性标记实验。简单来说,将来自批次1或批次2的hNLRP3与MCC7840或MCC950(25或50μM)或媒介物预孵育15min,随后与IZ1201或IZ1438(1μM)一起孵育1h,且这之后进行标准光亲和性标记程序。由探针特异性标记的蛋白质为在使用用作竞争物的母体化合物预处理的样品中展现凝胶内荧光信号减少的那些蛋白质。如图2B中所示,MCC950和MCC7840两者微弱地且实际上不一致地抑制IZ1201光并入到来自批次1和批次2的hNLRP3中。在另一方面,两种竞争物都以剂量依赖性方式以类似效力(在25μM下为约23%抑制且在50μM下为约37%抑制)阻断来自批次1的hNRLP3的IZ1438标记。然而,MCC950甚至在高剂量下微弱地防止IZ1438对来自批次2的hNLRP3的标记(在50μM下为11%抑制),而MCC7840产生以良好效力(在50μM下为约70%抑制)将IZ1438光并入到hNLRP3中的剂量依赖性抑制(图2C)。
综上所述,这些数据显示两种探针IZ1201和IZ1438结合至重组hNLRP3,且母体化合物MCC7840阻断其结合以及NLRP3特定抑制剂MCC950。我们因此推断IZ1201和IZ1438是研究MCC7840和类似物与hNLRP3的相互作用的可行的光亲和性探针。关于MCC7840与hNLRP3的结合位点的进一步研究将在来自批次2的hNLRP3上进行,其中IZ1438作为所选探针且MCC7840作为竞争物。
映射具有重组hNLRP3的IZ1438修饰的肽
为鉴定由IZ1438光标记的确切残基,单独或用与或不与MCC7840(50μM)组合的IZ1438(25μM)光照射hNLRP3(批次2,0.94μM)。在光解之后,使用SDS-PAGE解析样品并且用考马斯蓝将蛋白质染色。将对应于hNLRP3的蛋白质带从凝胶中切除,并且使其经历凝胶内胰蛋白酶蛋白水解。
图3:对应于hNLRP3的凝胶带中鉴定的蛋白质的等级次序分布。A,将包括hLNRP3的172种蛋白质分别用红色(hNLRP3)和蓝色(Sf21蛋白质)圆圈表示。将蛋白质从丰度最高(右)到丰度最低(左)评级。B,6His-SUMO-TEV-NLRP3(125-1036)的序列覆盖率图。由LC-MS/MS鉴定的肽以红色显示。6His-SUMO-TEV标签的序列以黄色突出显示。
总的来说,鉴定172种蛋白质,包括hNLRP3以及171种Sf21蛋白质。172种蛋白质基于其强度的等级次序分布示于图4A中。毫不意外,hNLRP3为凝胶带中定量的最强蛋白质。对于所有样品,实现hNLRP3的至少90%的序列覆盖率(图3B)。
通过LC-MS/MS分析所得肽。针对包括重组hNLRP3和草地贪夜蛾蛋白质序列的复合蛋白质数据库通过MaxQuant检索MS数据,其中IZ1438作为对任何氨基酸的修饰。由于光化学共轭的性质,结合位点可以由一种或多种肽上的若干氨基酸残基的多个共轭事件表示。人工验证分配到共轭肽的所有肽谱匹配(peptide spectral match;PSM)。使用实施于标准搜索中的MaxQuant中的“依赖性肽”设置来鉴定具有未知修饰的肽。在存在竞争物MCC7840的情况下在用探针IZ1438照射的样品中还鉴定出这种肽加合物,但其峰强度比用单独探针光标记的样品低2倍。正如所预期,未在对照样品(在不存在IZ1438的情况下UV照射的hNLRP3)中检测到对应于来自IZ1438修饰的195TCESPVSPIK204峰的双电荷信号的778.3711m/z处的前体离子(图4A)。对应于双电荷完整肽195TCESPVSPIK204的559.2817m/z处的基峰比对应的探针修饰肽强约1,000倍,从而指示hNLRP3的结合位点中IZ1438的特定共价光并入的产率较低(图4B)。
图4:在用与MCC7840竞争的IZ1438进行重组hNLRP3标记之后完整的和IZ1438修饰的hNLRP3肽:195TCESPVSPIK204的MS1强度值。通过LC-MS/MS分析检测具有来自hNLRP3的氨基酸序列TCESPVSPIK的独特胰蛋白酶肽,其中肽质量增加为+438.1727m/z,对应于将IZ1438并入到这个片段中。A,对应于不同样品中IZ1438修饰的TCESPVSPIK的778.3711m/z(z=2)处的前体离子的MS1强度值。B,当用IZ1438标记hLNRP3时检测的分别对应于完整和IZ1438修饰的TCESPVSPIK的559.2817m/z(z=2)和778.3711m/z(z=2)处的前体离子的MS1强度值。
MS1数据的检查显示,IZ1438修饰的195TCESPVSPIK204片段比未经修饰的对应物更晚洗脱(分别为178min和49min),从而表明在IZ1438的共价连接之后,肽加合物更具疏水性且因此更好地保留在C18管柱上。针对特异性探针标记的b型或y型片段离子的存在和光加合物(到特定氨基酸残基)的位点定位人工评估探针修饰的肽(778.3711m/z,z=2)和未经修饰的形式(559.2817m/z,z=2)的MS2光谱。除了在探针修饰的肽的MS2光谱中检测到质量为856.4772m/z且在未经修饰的肽的MS2光谱中检测到质量为1121.5302m/z的y8片段离子以外,两种肽形式共享若干b型和y型片段离子(图5A)。这个+265.0582m/z的质量偏移是由在CID片段化后连接到肽的探针的裂解产生的。
实际上,如图5B中所示,IZ1438于甲醇中的CID片段化产生两个由脲键联的裂解产生的片段离子:六氢-均-吲哒生-4-胺10(174.1282m/z)和用含最少末端炔烃双吖丙啶交联剂修饰的异氰酸1H-吡唑-3-磺酰酯11(294.0661m/z)。连接到y8片段离子的加合物的质量对应于在N2损失之后含有光交联剂的异氰酸1H-吡唑-3-磺酰酯片段的质量(294.0661m/z)。探针修饰的肽和其完整对应物的MS2分析将265.0582m/z的加合物的位点定位于E197。另外,MS2光谱的仔细检查还显示质量为174.1126m/z的片段离子,其仅存在于探针修饰的肽的MS2光谱中(图5A)。这个片段离子可能对应于六氢-均-吲哒生-4-胺,其在CID片段化时在光加合物裂解之后释放。我们的发现表明IZ1438以MCC7840可抑制方式光标记hNLRP3中的谷氨酸盐197。
图5:hNLRP3的完整或IZ1438修饰的肽TCESPVSPIK的MS2光谱:A,探针修饰的肽778.3711m/z和其完整对应物559.2817m/z的MS2光谱。探针修饰的肽的y8片段离子携带对应于在CID片段化时来源于IZ1438的加合物11的特定修饰(+265.0582m/z)且定位于E197(Emod)上。另外,仅在探针修饰的肽的MS2光谱中检测到从IZ1438裂解的片段离子174.1126m/z。B,显示特定子片段174.1274m/z和294.0646m/z的IZ1438的MS2光谱(放大的MS2光谱)。
结论
我们使用两种具有含最少末端炔烃双吖丙啶光交联剂的新颖光亲和性探针IZ1201和IZ1438在重组hLNRP3上成功地进行PALMS,并且显示出两种活性探针都以可保护方式用MCC7840和MCC950(NLRP3炎性体的有效和选择性抑制剂)光标记hNLRP3。这些结果显示MCC7840和MCC950体外结合hNLRP3。在IZ1438与MCC7840竞争的情况下使用PAL-MS,我们将交联氨基酸E197鉴定为hNLRP3中MCC7840的结合位点的部分。据我们所知,这是第一次在hNLRP3上应用光亲和性标记,以通过质谱阐明氨基酸分辨率下的交联位置。我们的发现表明化学蛋白质组学将结合位点映射到与例如MCC7840的新抑制剂相互作用的hNLRP3上的可能性。
设备
-Spectramax Paradigm(Molecular devices)
-PowerPac 200(Bio-Rad)
-离心机1-15pk(Sigma)
-ChemiDocTM MP成像系统(Bio-Rad)
-Q-Exactive Plus(ThermoFisher Scientific)
-nanoACQUITY UPLC系统(Waters)
-Ultimate 3500RSLC系统(Dionex)
-Orbitrap Velos Elite(Thermo Fisher Scientific)
-UVP CL-1000UV交联室(Hyland Scientific)
文献
1.Cox J,Mann M.MaxQuant enables high peptide identification rates,individualized p.p.b.-range mass accuracies and proteome-wide proteinquantification.Nat Biotechnol.2008 Dec;26(12):1367-72.doi:10.1038/nbt.1511.
2.Elias JE,Gygi SP.Target-decoy search strategy for increasedconfidence in large-scale protein identifications by mass spectrometry/NatMethods.2007Mar;4(3):207-14.
3.Cox J,Hein MY,Luber CA,Paron I,Nagaraj N,Mann M.Accurate proteome-wide label-free quantification by delayed normalization and maximal peptideratio extraction,termed MaxLFQ.Mol Cell Proteomics.2o14 Sep;13(9):2513-26.doi:10.1074/mcp.M113.031591.Epub 2014Jun 17.
4.Li Z,Hao P,Li L,Tan CY,Cheng X,Chen GY,Sze SK,Shen HM,Yao SQ.Designand synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell-andtissue-based proteome profiling.Angew Chem Int Ed Engl.2o13 Aug 12;52(33):8551-6.doi:10.1002/anie.201300683.
实施例2:以竞争性放射性配体分析型式评估结合至HEK-NLRP3裂解物上清液的化合物
目标为研发利用[H3]-MCC7840和过表达NLRP3的HEK293细胞裂解物的放射性配体结合分析。由于NLRP3为细胞质蛋白质,所以常规过滤结合分析方法不可用于从细胞溶解物中分离游离与结合的放射性标记。基于文献方法(Analytical Biochemistry308,2002127-133)评估凝胶过滤方法,且优化分析以评估工具化合物。
分析方案
上清液制备
将细胞团粒在冰上解冻且用结合缓冲液稀释二分之一。将所得溶液等分到1.5mlEppendorf管中并且离心(13.3g×1000,5分钟,在室温下)。去除上清液并且将其存储于-20℃下。使用Pierce BCA试剂盒,遵循制造商的说明书对这些样品进行蛋白质测定。
蛋白质分离和蛋白质印迹
在含有蛋白酶和磷酸酶抑制剂的RIPA裂解缓冲液中制备细胞上清液且使用单探针超声进行超声处理。BCA分析用于测定蛋白质浓度。随后使用十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)在4-12%Bis-Tris凝胶上分离含有等量蛋白质的蛋白质裂解物的体积并且使用iBLOT凝胶传送系统传送到硝酸纤维膜。
随后将印迹在odyssey封闭缓冲液中封闭1小时,且随后与初级抗体在4℃下在Tris缓冲盐水,0.1%Tween 20(TBST)中孵育过夜。随后将印迹在TBST中洗涤三次且在室温下与共轭IRDye的山羊抗兔或抗小鼠IgG二级抗体一起孵育1.5小时。使用Odyssey Li-Cor红外成像系统使免疫反应带可视化。
放射性配体结合分析
100μl的最终分析体积
细胞上清液体积取决于细胞上清液的每个批次的蛋白质浓度。
10ul 2μM[3H]-MCC7840(最终分析浓度(FAC)=200nM)
10ul化合物/非特异性结合(NSB)(10μM MCC7840,FAC 10μM)/DMSO对照(FAC DMSO=0.1%)
结合缓冲液体积取决于分析中所使用的上清液的体积。将样品组合在一起并且在震荡下在室温下孵育4小时。
PD MultiTrap G-25制备板(最终凝胶过滤方法)
凝胶过滤根据分子穿过填充在管柱中的凝胶过滤介质时的大小差异来分离分子。凝胶过滤介质由具有限定排除限制的球形粒子(例如葡聚糖凝胶(Sephadex))构成。当样品和缓冲液移动通过管柱时,分子扩散到孔隙中并且从孔隙中扩散出去。较小分子进一步移动到孔隙中,因此在管柱中保留更长时间。较大分子无法扩散到孔隙中,因此洗脱更快。简单来说,将PD MultiTrap板在室温(RT)、800g下快速离心1分钟以去除存储缓冲液。其用300微升/孔结合缓冲液洗涤五次,800g、室温持续1分钟。
每孔添加80μl样品,在400g下快速离心1分钟。将50μl流通物添加到Optiplate中的145μl Microscint-20中。在Perkin Elmer TopCount中读数之前,将板在室温下振荡大致30分钟。使用GraphPad Prism分析数据。
过表达HEK细胞溶解物中NLRP3蛋白质的确认在HEK293细胞溶解物中使用如上文所描述的蛋白质印迹确认NLRP3表达。以1:1000使用来自Cell Signalling Technologies的NLRP3兔抗体(#15101),以1:5000稀释使用GAPDH抗体,以1:10000稀释使用Alexa-fluor山羊抗兔800。使用Licor红外成像系统对蛋白质印迹(western)进行成像。图6:确认在过表达HEK细胞的上清液(A)中和管柱洗脱级分(B)中存在NLRP3。将多个裂解缓冲液(PBS,具有和不具有蛋白酶和磷酸酶抑制剂的RIPA)进行比较且显示相当的结果。还在相同凝胶上比较来自用脂多糖刺激的THP-1细胞的裂解物(A),但在这些样品中未检测到带。这可归因于如下事实:如针对GAPDH检测到的较低强度带所示,从这些样品中提取和负载量低得多的蛋白质。较高量的蛋白质负载显示对应于NLRP3的恰当大小的带(B),但这并不因脂多糖刺激而增加。在负载之前且根据PD MultiTrap G-25制备板的洗脱级分比较HEK293-NLRP3上清液样品(B),以确认洗脱液中NLRP3的存在。
图7:使用两种不同抗体确认在过表达HEK细胞的上清液中存在NLRP3和在对照未转染的HEK细胞中不存在NLRP3(A和B);相较于未转染的对照,在所转染的HEK细胞中检测到NLRP3表达的大于2000倍增加,n=3个独立实验(C)。
PD MultiTrapTM G-25方法的优化
通过一系列实验优化结合与游离放射性标记的分离,所述实验研究各种离心方案和不同缓冲液制剂。通过真空移动样品的尝试证明管柱太长而无法实现这个程序。然而,通过降低自旋的速度,有可能减少NSB且获得大致三倍的分析窗口(图8:左侧图:800g,20秒;右侧图:400g,1min)。
组织线性
通过改变细胞上清液的蛋白质在放射性配体结合分析中的浓度来进行组织线性实验。使用10μM未标记化合物MCC7840限定非特异性结合。通过从总结合减去非特异性结合来确定特异性结合。将具有良好分析窗口的最低浓度测定为每孔700μg蛋白质。这是用于所有后续实验的蛋白质浓度(图9:放射性配体结合研究(200nM[3H]-MCC7840,4小时,在室温下)组织线性(n=3))。
未转染的相对于NLRP3转染的HEK细胞上清液的比较
使用未转染的且经NLRP3转染的细胞上清液测定分析信号。如图5中所示,通过比较分析中未转染的HEK293细胞上清液和过表达NLRP3的细胞上清液的总结合和非特异性结合来进行背景信号的评估。相较于未转染的对照上清液,200nM[3H]-MCC7840的总结合在NLRP3细胞上清液中增加了大致三倍(图10:放射性配体结合研究(700μg蛋白质,200nM[3H]-MCC7840,4小时,在室温下)。
放射性配体饱和结合研究
通过在三个独立实验中改变200倍范围内的浓度来进行[3H]-MCC7840的饱和结合研究以测定Kd。组合由三个单独实验测试的所有浓度以获得更精确的Kd(图6e)。[3H]-MCC7840的Kd由三个独立实验测定为大致230nM(图11)。
ATP和ADP的放射性配体竞争结合研究
为了说明配体结合是否与ATP和ADP竞争,通过改变ATP和ADP的浓度并且在200nM下与[3H]-MCC7840竞争来进行实验。尽管看到与ATP的一些竞争,但不可测试更高浓度来限定完整的浓度效应曲线。通过限制ATP曲线拟合中的最小值获得75mM的估计IC50(图12:放射性配体结合研究(700μg蛋白质,200nM[3H]-MCC7840,4小时,在室温下))。
结论
在这个报道中呈现的数据显示了新颖的基于96孔板的凝胶过滤结合分析的成功研发,所述分析用于测量放射性配体与过表达NLRP3的HEK293细胞裂解物上清液中的NLRP3的结合。分析用于测定NLRP3放射性配体[3H]-MCC7840的结合特征。
试剂
结合缓冲液组成:
50mM Tris HCl(7.88g/l)
120mM NaCl2(24mls,5M/l)
5mM KCl(0.372g/l)
1mM EDTA(0.292g/l)
pH 7.4
实施例3:模型化
创建数字构建体以提供探测NRLP3蛋白质的新颖方式,从而提供对NLRP3抑制剂的结合位点的机制性见解。
使用手动构建的氨基酸序列比对,由小鼠NLRC4和兔NOD2蛋白质(pdb代码分别为4kqv和5irn)的X射线晶体结构NACHT结构域构建人类NLRP3的多个模型。分析这些以鉴定可能的配体结合位点(使用来自MolSoft L.C.C的算法):参见图13,其显示具有预测配体结合位点的NLRP3模型中的一个。最大且最有可能的结合位点为口袋1,并且始终最有可能的小分子结合位点处于与来自NLRC4和NOD2晶体结构的ADP等效的位置:参见图14,其为预测最可能的配体结合位点,与NLRC4和NOD2结构两者的ADP的X射线晶体学结构重叠的NLRP3模型。对最可能的结合位点的预测涵盖ADP分子的X射线晶体学结构位置。ATP结合位点将具有相同位置。
NLRC4和NOD2的X射线晶体结构显示Walker A基序结合磷酸基,进一步通过相邻的组氨酸残基(NLRC4中的His443和NOD2结构中的His583)稳定。人类NLRP3、His522以及Walker A结合基序中存在等效的组氨酸残基,其限定NLRP3中ATP/ADP的等效磷酸盐结合位点。小分子抑制剂MCC950含有模拟磷酸基的磺酰基脲部分,且当模型化到蛋白质中时,定位分子以填充由口袋1限定的更多空间:参见图15,其显示模型化到活性位点中的MCC950,其中磺酰基脲基位于Walker A基序与His522残基之间。
实施例4:诱变数据
将与隐热蛋白相关周期性综合征(CAPS)相关的突变的选择鉴定为接近NLRP3的活性位点:参见下文的图16和表C。
表C
hNLRP3临床变体编号 |
T348M |
G301D |
W414L |
M521T |
I480F |
R260W/L/P |
E304K |
D303N/A/H/G |
C259W |
A352V/T |
在记录来自临床医师和一些研究人员的CAP突变的数据库(https:// infevers.umai-montpellier.fr/web/search.php?n=4)中,残基编号为来自如Uniprot的蛋白质数据库(https://www.uniprot.org/uniprot/Q96P20)中的NLRP3的蛋白质序列的-2个氨基酸。对于本申请中的计算模型,已使用Uniprot中的参考序列。临床突变注解包括于本申请中的唯一位置为表C。
预期下表D中详述的NLRP3突变中的一个或多个将防止NLRP3抑制剂的结合,使NLRP3蛋白质呈现无活性,使NLRP3蛋白质呈现组成性活性和/或提供对结合口袋的结构见解。
表D
应当理解,上文仅以实施例的方式描述了本发明。所述实施例并不意欲限制本发明的范围。
在不脱离仅由所附权利要求书限定的本发明的范围和精神的情况下,可以进行各种修改和实施方案。
Claims (26)
1.一种NLRP3炎性体的结合位点,其中所述结合位点:
(a)在所述NLRP3炎性体的Walker A和/或Walker B位点处或附近;和/或
(b)包含一个或多个选自以下的残基:Arg183、Gly229、Ile230、Gly231、Lys232、Thr233、Ile234、Gly303、Asp305、Glu306、Leu413和His522。
2.一种抑制NLRP3活化的方法,所述方法包括使化合物与权利要求1所述的结合位点结合的步骤。
3.一种用于抑制NLRP3活化的化合物,其中所述化合物适于与权利要求1所述的结合位点结合。
4.一种治疗对NLRP3抑制有响应的疾病、病症或疾患的方法,所述方法包括使治疗有效量的化合物与权利要求1所述的结合位点结合的步骤。
5.一种用于治疗对NLRP3抑制有响应的疾病、病症或疾患的化合物,其中所述化合物适于与权利要求1所述的结合位点结合。
6.一种用于治疗对NLRP3抑制有响应的疾病、病症或疾患的化合物,其中所述化合物为权利要求1所述的结合位点的拮抗剂。
7.如权利要求4所述的方法或如权利要求5或6所述的化合物,其中所述疾病、病症或疾患选自:
(i)炎症;
(ii)自身免疫疾病;
(iii)癌症;
(iv)感染;
(v)中枢神经系统疾病;
(vi)代谢疾病;
(vii)心血管疾病;
(viii)呼吸疾病;
(ix)肝病;
(x)肾病;
(xi)眼部疾病;
(xii)皮肤病;
(xiii)淋巴疾患;
(xiv)心理障碍;
(xv)移植物抗宿主病;
(xvi)疼痛;
(xvii)与糖尿病相关的疾患;
(xviii)与关节炎相关的疾患;
(xix)头痛;
(xx)创伤或烧伤;和
(xxi)其中已确定个体携带NLRP3的种系或体细胞非沉默突变的任何疾病。
8.如权利要求4所述的方法或如权利要求5或6所述的化合物,其中所述疾病、病症或疾患选自:
(i)隐热蛋白相关周期性综合征(CAPS);
(ii)穆-韦二氏综合征(MWS);
(iii)家族性冷因性自身炎症综合征(FCAS);
(iv)新生儿发作型多系统炎症性疾病(NOMID);
(v)家族性地中海热(FMF);
(vi)化脓性关节炎、坏疽性脓皮病和痤疮综合征(PAPA);
(vii)高免疫球蛋白血症D和周期性发热综合征(HIDS);
(viii)肿瘤坏死因子(TNF)受体相关周期性综合征(TRAPS);
(ix)全身性幼年性特发性关节炎;
(x)成人发作型斯蒂尔氏病(AOSD);
(xi)复发性多软骨炎;
(xii)薛尼兹勒氏综合征;
(xiii)斯维特氏综合征;
(xiv)白塞氏病;
(xv)抗合成酶综合征;
(xvi)白介素1受体拮抗剂缺乏症(DIRA);和
(xvii)A20单倍剂量不足(HA20)。
9.一种通过抑制NLRP3活化来减少细胞或线粒体活性氧物质(ROS)的方法,所述方法包括使化合物与权利要求1所述的结合位点结合的步骤。
10.一种用于通过抑制NLRP3活化来减少细胞或线粒体活性氧物质(ROS)的化合物,其中所述化合物适于与权利要求1所述的结合位点结合。
11.如权利要求2至10中任一项所述的方法或化合物,其中所述化合物为小分子、肽、多肽、寡核苷酸、蛋白质、抗体或适体。
12.如权利要求2至11中任一项所述的方法或化合物,其中所述化合物适于与所述结合位点共价或非共价结合。
13.如权利要求2至12中任一项所述的方法或化合物,其中所述化合物实现对NLRP3活化的抑制且由此防止ATP从所述NLRP3的Walker A和/或Walker B位点取代ADP。
14.如权利要求2至13中任一项所述的方法或化合物,其中所述化合物通过与一个或多个选自以下的残基结合而实现对NLRP3活化的抑制:Arg183、Gly229、Ile230、Gly231、Lys232、Thr233、Ile234、Gly303、Asp305、Glu306、Leu413和His522。
15.如权利要求2至14中任一项所述的方法或化合物,其中所述化合物包含充当膦酸酯模拟物的基序。
16.一种筛选化合物的方法,所述方法包括以下步骤:(i)使所述化合物暴露于权利要求1所述的结合位点,和(ii)测定所述化合物与所述结合位点的结合程度。
17.如权利要求16所述的方法,其中所述化合物与所述结合位点的结合程度通过质谱、NMR、X射线晶体学、SPR或放射性配体结合来测定。
18.一种筛选化合物的方法,所述方法包括以下步骤:(i)在计算机上模拟使所述化合物暴露于权利要求1所述的结合位点,和(ii)测定所述化合物与所述结合位点的结合程度。
19.一种通过权利要求16至18中任一项所述的方法鉴定的化合物,或其药学上可接受的盐、溶剂合物或前药。
20.一种适于与权利要求1所述的结合位点结合的化合物,或其药学上可接受的盐、溶剂合物或前药。
21.一种药物组合物,其包含权利要求19或20所述的化合物或药学上可接受的盐、溶剂合物或前药,和药学上可接受的赋形剂。
22.如权利要求19或20所述的化合物或药学上可接受的盐、溶剂合物或前药或权利要求21所述的药物组合物,其用于药物中。
23.如权利要求22所述的化合物、药学上可接受的盐、溶剂合物、前药或药物组合物,其用于治疗或预防疾病、病症或疾患,其中所述疾病、病症或疾患对NLRP3抑制有响应。
24.如权利要求22或23所述的化合物、药学上可接受的盐、溶剂合物、前药或药物组合物,其用于治疗或预防疾病、病症或疾患,其中所述疾病、病症或疾患选自:
(i)炎症;
(ii)自身免疫疾病;
(iii)癌症;
(iv)感染;
(v)中枢神经系统疾病;
(vi)代谢疾病;
(vii)心血管疾病;
(viii)呼吸疾病;
(ix)肝病;
(x)肾病;
(xi)眼部疾病;
(xii)皮肤病;
(xiii)淋巴疾患;
(xiv)心理障碍;
(xv)移植物抗宿主病;
(xvi)疼痛;
(xvii)与糖尿病相关的疾患;
(xviii)与关节炎相关的疾患;
(xix)头痛;
(xx)创伤或烧伤;和
(xxi)其中已确定个体携带NLRP3的种系或体细胞非沉默突变的任何疾病。
25.如权利要求22或23所述的化合物、药学上可接受的盐、溶剂合物、前药或药物组合物,其用于治疗或预防疾病、病症或疾患,其中所述疾病、病症或疾患选自:
(i)隐热蛋白相关周期性综合征(CAPS);
(ii)穆-韦二氏综合征(MWS);
(iii)家族性冷因性自身炎症综合征(FCAS);
(iv)新生儿发作型多系统炎症性疾病(NOMID);
(v)家族性地中海热(FMF);
(vi)化脓性关节炎、坏疽性脓皮病和痤疮综合征(PAPA);
(vii)高免疫球蛋白血症D和周期性发热综合征(HIDS);
(viii)肿瘤坏死因子(TNF)受体相关周期性综合征(TRAPS);
(ix)全身性幼年性特发性关节炎;
(x)成人斯蒂尔氏病(AOSD);
(xi)复发性多软骨炎;
(xii)薛尼兹勒氏综合征;
(xiii)斯维特氏综合征;
(xiv)白塞氏病;
(xv)抗合成酶综合征;
(xvi)白介素1受体拮抗剂缺乏症(DIRA);和
(xvii)A20单倍剂量不足(HA20)。
26.一种抑制NLRP3活化的方法,所述方法包括使用权利要求19或20所述的化合物或药学上可接受的盐、溶剂合物或前药或权利要求21所述的药物组合物来抑制NLRP3活化。
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