CN113563414A - 一种组织靶向的蛋白靶向降解化合物及其用途 - Google Patents
一种组织靶向的蛋白靶向降解化合物及其用途 Download PDFInfo
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Abstract
本发明公开了一种组织靶向的蛋白靶向降解化合物及其用途，涉及制药领域，更具体而言涉及这样一种化合物或其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。该化合物为具备组织靶向能力的蛋白靶向降解嵌合体。该化合物结构包括3部分：A‑BD‑CON，其中A部分为蛋白靶向降解嵌合体(PROTAC)，其结构一端为靶蛋白结合配体，另一端为泛素连接酶配体；CON部分为去唾液酸糖蛋白受体(ASGPR)的配体，具备使PROTAC特定组织靶向的功能。本发明在成药难度很大的蛋白靶向降解嵌合体(PROTAC)基础上，进一步实现了肝脏组织富集和细胞靶向的功能，提高了PROTAC溶解性、细胞通透性和在特定靶组织的药效，从而总体上提高了其成药性。
Description
技术领域
发明涉及制药领域，更具体而言涉及这样一种化合物或其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。该化合物为具备组织靶向能力的蛋白靶向降解嵌合体。该化合物结构包括3部分：A-BD-CON，其中A部分为蛋白靶向降解嵌合体(PROTAC)，其结构一端为靶蛋白结合配体，另一端为泛素连接酶配体；CON部分为去唾液酸糖蛋白受体(ASGPR)的配体，具备使PROTAC特定组织靶向的功能。本发明在成药难度很大的蛋白靶向降解嵌合体(PROTAC)基础上，进一步实现了肝脏组织富集和细胞靶向的功能，提高了PROTAC溶解性、细胞通透性和在特定靶组织的药效，从而总体上提高了其成药性。
背景技术
肿瘤作为全球范围内发病率和死亡率都很高的一种疾病,严重威胁着人类健康,成为世界各国面临的重要社会问题之一。肝癌是我国第四大高发肿瘤，每年新增肝癌患者约46万人，也是我国第二大死亡率的肿瘤(死亡率26/10万)。在世界范围内，每年有超过84万的新发肝癌病例，中国每年新发肝癌病例约占全球的50％。肝癌缺乏有效药物，其五年生存率仅为10％。肝癌防治形势非常严峻。
肝炎是另一个主要的肝部疾病，在我国主要是乙型肝炎。目前我国乙肝病毒携带者在9000万人左右。世界卫生组织发布，全球仅8％乙肝患者获得抗病毒治疗，我国约10％。泛素介导的蛋白质降解是细胞内蛋白质最主要的负向调节方式。泛素化降解途径可以降解细胞内80％～90％泛素化的蛋白质,参与调节细胞周期、增殖、凋亡、转移、基因表达、信号传递等几乎一切生命活动。该过程是在泛素激活酶E1、泛素结合酶E2和泛素连接酶E3的协同作用下进行,底物蛋白被泛素化后,在蛋白酶体中被降解,依靠泛素连接酶E3对底物蛋白特异的识别能力,决定了泛素介导的蛋白降解具有特异性。PROTACs本质上是一种杂合双功能小分子化合物,其结构有三部分组成:泛素连接酶E3配体,目标靶蛋白结合配体,两个配体之间通过连接物相连。PROTACs通过将目标靶蛋白和细胞内的E3拉近,形成靶蛋白-PROTACs-E3酶,通过E3泛素连接酶给目标靶蛋白加上泛素化蛋白标签,启动细胞内强大的泛素化水解过程,利用泛素-蛋白酶体途径特异性地降解靶蛋白，达到治疗疾病的目的。
CN108601764A公开了一系列用于PROTAC中的作为E3泛素连接酶配体的VHL配体结构。
与传统药物“占位驱动”型(即需持续占据靶蛋白的活性位点以阻断其功能)发挥作用不同，PROTAC与靶蛋白接触时，只需提供结合活性，触发靶蛋白与E3连接酶结合从而引发降解这一事件，属于“事件驱动”，无需与目标蛋白长时间和高强度的结合。因此，PROTAC可以靶向传统难以成药的靶点，比如表面光滑缺乏小分子结合区域的蛋白，很多无法用小分子或抗体靶向的靶点可以用PROTAC技术靶向。PROTAC分子只需要短暂与靶蛋白表面结合，即可诱导靶蛋白泛素化及降解，该过程不受传统均衡占有率的限制，更类似于一种催化行为，可重复使用。
PROTAC理论上具有如下优势：用量小，催化剂量即可，药物安全窗口大；克服因靶蛋白突变/过表达引起的耐药；不依赖亲和力，选择性高；清除蛋白堆积。
虽然PROTAC有着以上种种优势，但其存在的主要问题是成药性。
PROTAC的分子量一般都在700以上，打破了传统小分子药物化学的成药原则。对于三联体的PROTAC而言，无论从分子量上还是复杂性上都违背了小分子成药原则，因此在成药性上不可避免存在许多挑战，如水溶性、通透性、PK/PD等等。脱靶毒性也是普遍关注的问题。PROTAC是事件驱动型催化反应，其是否对于正常组织上表达靶蛋白有影响是未知的。
去唾液酸蛋白受体(asialoglycoprotein receptor,ASGPR)是肝细胞特异性表达的一种内吞型受体，可特异性识别与结合具有非还原性D-半乳糖(β-D-galactose,Gal)或N-乙酰半乳糖胺(N-acetylgalactosamine,GalNAc)作为末端糖基的去唾液酸N链接糖蛋白，尤其是三簇、四簇糖蛋白。近年来，利用ASGPR的高亲和性配体GalNAc作为靶向分子，在核酸药物的肝靶向递送方面取得了突破性进展，如通过使包含末端半乳糖或其衍生物的缀合部分连接至核酸，从而使该核酸分子通过结合ASGPR靶向至肝细胞，参见，例如WO2009/073809、WO2011/104169和WO2012/083046，而关于ASGPR配体的其他方面的应用和研究目前尚未见报道。
发明内容
为了克服现有技术中PROTAC化合物的上述缺陷，本发明创造性地将去唾液酸糖蛋白受体(ASGPR)的配体与PROTAC化合物相结合，通过特定设计的连接基团，意外地发现提高了化合物的溶解性、细胞通透性和在肝组织的药效，并且实现该化合物向肝组织富集和细胞靶向，利用细胞的内吞功能及溶酶体作用分解为PROTAC和ASGPR的配体。ASGPR受体再循环回到细胞表面，PROTAC实现降解靶标蛋白的功效，从而对于PROTAC而言实现并提高了跨膜转运，提高了在肝组织的药效，从而总体上提高了其成药性。
本发明提供这样一种化合物或其药学上可接受的盐、立体异构体、溶剂化物或多晶型物。该化合物为溶解性提升、具备组织靶向能力和更高成药性的蛋白靶向降解嵌合体。
该化合物结构包括3部分：A-BD-CON，其中A部分为蛋白靶向降解嵌合体(PROTAC)，A部分的结构一端为靶蛋白结合配体，另一端为泛素连接酶配体；CON部分为为去唾液酸糖蛋白受体(ASGPR)的配体，发挥提高溶解性、使PROTAC特定组织和细胞的靶向功能、提高成药性等综合功能。本发明是通过以下方面实现的：
本发明的第一个方面：
本发明提供了一种具有如下结构的化合物或其药学上可接受的盐、立体异构体、溶剂化物或多晶型物，所述化合物由以下三部分组成：
A-BD-CON
其中CON为去唾液酸糖蛋白受体(ASGPR)的配体,
A为LGP-Y-Z-LK-LGE的结构,
其中，LGP为靶蛋白结合配体，LGE为E3泛素连接酶配体；
Y，Z分别独立地是共价键，CH2，C1-C4烷基取代的亚甲基，NH，C1-C4烷基取代的氮原子，O或者S；当Y选自O，S，NH或C1-C4烷基取代的氮原子时，Z选自共价键，CH2，C1-C4烷基取代的亚甲基；当Z选自O，S，NH或C1-C4烷基取代的氮原子时，Y选自共价键，CH2，C1-C4烷基取代的亚甲基；
LK一端通过Y-Z与LGP连接，另一端通过共价键与LGE连接，LK特征为选自如下结构单元：
其中m任选为0-5的自然数；n任选为0-20的自然数；p任选为0-4的自然数；q任选为0-20的自然数；r任选为1-3的自然数；s任选为1-5的自然数；
X任选是CH2、O，S,NR1，R1任选为H、C1-6烷基、C1-6卤代烷基或者C1-6烷氧基取代的C1-6烷基；
BD为A与CON的连接物，特征为具有Q-LN的结构；其中Q在细胞内的内体或溶酶体内水解酶酸性条件下可以降解断裂，释放A；Q的结构包括腙、脲，肟，二硫基、硫醚、酰胺、酯(羧酸酯、磷酸酯、焦磷酸酯、碳酸酯、硫酸酯、磺酸酯、氨基磺酸酯、亚甲基磺酸酯、氨基甲酸酯),或者
LN为Q与CON之间的连接基团，选自3-20个碳原子的碳链，其中任意的CH2可被O、NH、C(O)取代。
本发明的第二个方面：
发明的第一方面所述及的化合物的特征在于所述的LGE为泛素化E3酶的配体，优选为Von Hippel–Lindau肿瘤抑制因子(Von Hippel–Lindau tumor suppressor,pVHL)的配体；进一步优选为如下通式表达的结构，
分子两端分别与LK和Q结构单元相连，LK与Q的定义与发明第一方面所述相同；G为C1-C10烷基，C3-C10环烷基，3-10元含有1-3个O、N、S原子的杂环烷基，优选异丙基，叔丁基，环己基或四氢吡喃；更优选叔丁基。
本发明的第三个方面：
发明第一，第二方面所述的化合物，其结构可由如下通式表示：
其中通式中Q选自如下结构单元：
通式中LN选自如下结构单元
其中V任选为自然数3-15；V优选的为自然数5-12，
通式中G为C1-C10烷基，C3-C10环烷基，3-10元含有1-3个O、N、S原子的杂环烷基，优选异丙基，叔丁基，环己基或四氢吡喃；更优选叔丁基，
通式中Y，Z与发明第一方面中所述Y，Z相同，
通式中LK独立地选自与发明第一方面中所述LK相同的结构单元。
本发明的第四个方面：
发明第一至第三方面所述的化合物，其特征在于CON结构特征表示如下：
其中S1-S3分别独立地选自如下结构单元：半乳糖、半乳糖胺、葡萄糖、葡萄糖胺、甘露糖、甘露糖胺、乳糖酸；其中包括D构型或L构型糖结构；
其中S1-S3通过阿尔法糖苷键或者贝塔糖苷键分别与L1-L3连接；
其中L1-L3分别独立地选自如下结构：化学键，C3-C15长度的脂肪碳链，C3-C15长度的在中间任意位置插入一个或多个O，S、NH或羰基的脂肪碳链；
其中M选自C，N，O，S，P(＝O)并与LN通过共价键连接；
其中S1-L1，S2-L2，或S3-L3可以分别独立地不存在。
本发明的第五个方面：
发明第一至第四方面所述的化合物，其特征在于所述CON选自以下的结构：
本发明的第六个方面：
发明第一至第三方面所述的化合物，其特征在于LGP选自如下结构单元：
其中R2-R5分别独立选自H，F，Cl，Br，C1-4烷基、C1-4烷氧基；R6选自H，C1-4烷基、C1-4烷氧基。
本发明的第七个方面：
本发明前述任一方面的化合物，其特征在于所述LGP为癌症相关靶点、微生物相关靶点、免疫疾病相关靶点、神经退行性疾病相关靶点、代谢类疾病相关靶点的配体。
本发明的第八个方面：
本发明前述的化合物，其特征在于LGP结合的靶点为激酶、转录因子、表观遗传阅读窗、微管相关蛋白、微生物相关蛋白等。
本发明的第九个方面：
本发明前述的化合物，其特征在于LGP结合的靶点为EGFR、VEGFR、FGFR、PDGFR、Raf、Braf、RET、FLT、c-Kit、MET、ACVR、ALK、AKT、AhR、AURKA、AR、RAR、ER、BCL、BCR-ABL、BET、BMPR、BLK、BTK、BRD、CDK、CK、CHEK1、CTNNB1、DDR、DHODH、RAS、EED、ESR1、CRABP、CRBN、HER2、HER3、HMGCR、Htt、GNA11、GNA1、GNAS、NQO、TROP、eIF4E、ERK、ERG、ETV、ERRα、EZH2、FAK、IDH1/2、IGF1R、IRAK4、JAK、MEK、MELK、LTK、FKBP、MDM2、HDAC、MER、MCL、MTOR、PAR、PBRM、PCAF、PDE、PD-1、PD-L1、PTK、PARP、PDXK、PLK、PKB、MAPK、PI3K、Pirin、RIPK、Rpn13、PRC、P38、TGFβ、AFP、NTRK、NHE、CEA、SOAT1、SNCA、SYK、RNF43、DLK1、gp96、SGK、SMAD、SMO、SFB、SHP、SIK、SRC、STAT3、TBK、TYK3、TRIM、NS3、IRAK4、PCAF、GCN5、Sirt2、Tau、TUB、Wee1、ZAK或者其组合靶点。
本发明的第十个方面：
本发明前述的化合物,其特征在于所述LGP为Hsp90抑制剂、激酶抑制剂、磷酸酶抑制剂、MDM2抑制剂、靶向含有人BET布罗莫结构域的蛋白的化合物、HDAC抑制剂、人赖氨酸甲基转移酶抑制剂、靶向RAF受体的化合物、靶向FKBP的化合物、血管生成抑制剂、免疫抑制性化合物、靶向芳基烃受体的化合物、靶向雄激素受体的化合物、靶向雌激素受体的化合物、靶向甲状腺激素受体的化合物、靶向HIV蛋白酶的化合物、靶向HIV整合酶的化合物、靶向HCV蛋白酶的化合物、靶向酰基蛋白硫酯酶1和/或2的化合物。
本发明的第十一个方面：
本发明前述的化合物，其特征在于所述LGP为：索拉非尼、乐伐替尼、瑞格非尼、卡博替尼、阿帕替尼、法瑞替尼、卡铂、顺铂、奥沙利铂、依维莫司、培美曲塞、厄洛替尼、达沙替尼、伊马替尼、舒尼替尼、奥西替尼、依布替尼、阿来替尼、克唑替尼、恩曲替尼、阿法替尼、阿西替尼、色瑞替尼、拉罗替尼、布加替尼、来那替尼、曲美替尼、拉帕替尼、纳拉替尼、5-氟尿嘧啶、依托泊苷、吉西他滨、地西他滨、卡培他滨、多柔比星、表柔比星、长春新碱、替莫唑胺、长春新碱、异环磷酰胺、米托蒽醌、吉非替尼、硼替佐米、紫杉醇、多西他赛、聚乙二醇化干扰素α-2a、干扰素α-2a、聚乙二醇化干扰素α-2b、干扰素α-2b、阿扎胞苷、阿糖胞苷、环胞苷、伊立替康、拓扑替康、阿糖腺苷、碘苷(IDU)、三氟胸苷、溴乙烯去氧尿苷、甘草酸镁、甘草酸苷、谷胱甘肽、多磷脂酰胆碱、腺苷蛋氨酸、熊去氧胆酸、乌司他丁。
本发明的第十二个方面：
本发明前述的化合物，其特征在于，代表性化合物具有以下的结构：
优选地，所述化合物具有WG-1、WG-2、WG-3、WG-4、WG-5、WG-6所示的结构。
本发明的第十三个方面：本发明提供了前面所述任一项化合物的药物组合物。
本发明的第十四个方面：本发明提供了前面所述任一项化合物及其药物组合物在制备治疗肿瘤药物中的应用，优选地所述肿瘤为肝癌。
本发明的第十五个方面：本发明提供了前面所述任一项化合物及其药物组合物在制备治疗肝部疾病药物中的应用，优选地所述肝部疾病为肝炎。
除非另外定义，本发明中使用的所有术语(包括技术术语和科学术语)均具有如本发明所属领域的普通技术人员通常理解的相同含义。
附图说明
图1 WG-1(00300639)的HPLC图谱。
图2 WG-1(00300639)的LC/MS图谱。
图3 WG-1(00300639)的1HNMR图谱。
图4 WG-1(00300639)的31PNMR图谱。
图5 WG-1(00300639)与WGint4(003006)的跨膜性测试。
图6 WG-1(00300639)、WGint4(003006)及阳性药乐伐替尼的癌细胞生长抑制测试。
图7 WG-1(00300639)、WGint4(003006)的蛋白降解测试。
具体实施方式
下面结合本发明说明书附图通过具体实施例进一步说明本发明。但是这些实施例仅仅是用于更详细的具体说明用，而不应理解为用于以任何形式限制本发明。本发明可以由权利要求限定和覆盖的多种不同方式实施。
本发明对试验中所使用到的材料以及实验方法进行一般性和具体性的描述。虽然为实现本发明的目的所使用的许多材料和操作方法是本领域公知的，但是本发明仍然在此作尽可能详细的描述。在下文中，如未特别说明，所使用的材料和操作方法是本领域公知的。
WG系列化合物可以通过如下的工艺路线或类似的工艺路线实现。其中，化合物WGint4为本发明通式结构中的A化合物，需要个性化合成，WGint8为本发明通式中的CON化合物，可参照现有技术进行合成或者从供应商处购买，其余步骤为共用或者类似路线。
以WG-1(00300639)为例，其合成路线如下：
相对于化合物WG-1(00300639)，其对应的WGint4为WGint4(003006)，WGint4(003006)合成路线如下所示：
相对于化合物WG-4(00500639)和WG-5(00600639)，对应的WGint4为WGint4(005000)和WGint4(006000)，其合成采用如下的方法：
(1)化合物side 1的合成
(2)化合物Core 1的合成
(3)化合物WGint4(006000)的合成
(4)化合物WGint4(005000)的合成
本申请范围内的其他化合物的合成均可参照上述路线，选择对应的原料进行制备。
实施例1、化合物WGint2的合成
用碳酸氢钾(5.32g，53.2mmol)和苄基溴(9.10g，53.2mmol)处理10-羟基癸酸(10.0g，53.2mmol)存于DMF(250mL)中的溶液，然后在室温下在氩气下搅拌18小时。蒸发溶剂，残渣在EA和水之间分配。水层用EA洗涤，合并的有机提取物用无水硫酸镁干燥。通过硅胶快速色谱法纯化所得粗品，得到白色固体形式的化合物WGint2(8.0g)，LC/MS(ESI)m/z:[M+H]+279。
实施例2、化合物WGint3的合成
向化合物WGint2(5.0g，18.0mmol)存于100mL含有四唑二异丙胺(4.6g，27.0mmol)的无水二氯甲烷中的溶液中添加2-氰基乙氧基-N，N，N，N-四异丙基二磷酸胺(9.0mL，27.0mmol)，并且在室温下搅拌该混合物6h，直到TLC显示完全反应。然后通过蒸发去除二氯甲烷，并在乙酸乙酯中提取产物，用5％碳酸氢钠溶液和盐水洗涤，在无水硫酸钠上干燥并蒸发至小体积。产物在硅胶柱上用10-35％乙酸乙酯-正己烷+2％三乙胺洗脱得到化合物WGint3(2.5g)。该中间体直接用于下一步反应。
实施例3、化合物WGint6的合成
将化合物WGint3(2.5g，5.2mmol)和化合物WGint4(0.5g，0.52mmol)在ACN(25mL)中的混合物加入四唑(145mg，2.1mmol)并搅拌过夜。在0℃下逐滴添加癸烷(2mL，5M)中的过氧化叔丁酯，并且在室温下将混合物搅拌6h。用薄层色谱法监测反应。反应完成后，反应混合物在40℃下浓缩，用EA稀释，用水和盐水溶液洗涤。有机层在无水Na2SO4上干燥，过滤并蒸发溶剂得到粗化合物WGint6。LC/MS(ESI)m/z:[M+H]+1360。
实施例4、化合物WGint7的合成
将上述步骤得到的粗化合物WGint6溶于THF(8mL)中。然后加入0.5m LIOH(8mL)。混合物在室温下搅拌6h，蒸发得粗品，用制备高效液相色谱法纯化得到化合物WGint7(85mg)。LC/MS(ESI)m/z:[M+H]+1218。
实施例5、化合物WGint9的合成
化合物WGint7(40mg，0.033mmol)在DMF(1mL)中加入HBTU(13.8mg，0.036mmol)和DIEA(4.7mg，0.036mmol)，搅拌几分钟。将化合物WGint8(40mg，0.022mmol)溶于DMF(0.5mL)中，室温搅拌过夜。减压除去溶剂和挥发物，用制备高效液相色谱法纯化残留物，得到化合物WGint9(8mg)。LC/MS(ESI)m/z:[M+H]+2993。
实施例6、化合物WG-1(00300639)的合成
用40％氨水(0.5mL)处理化合物WGint9(8mg)在甲醇(0.5mL)中的溶液，在室温下搅拌4h。将混合物蒸发后倒入水和DCM中，蒸发有机层得到化合物WG-1(00300639)(6毫克)。LC/MS(ESI)m/z:[M+H]+:2614，[M/2+1]+:1308；1HNMR(CD3OD,400MHz):δ8.887(s,1H),8.779(s,1H),8.638-8.651(d,J＝5.2Hz,1H),8.206-8.228(d,J＝8.8Hz,1H),7.388-7.509(m,5H),7.201-7.280(m,2H),6.608-6.622(d,J＝5.6Hz,1H),4.537-4.682(m,3H),4.358-4.398(t,J＝16.0Hz,3H),4.086-4.113(t,J＝10.8Hz,3H),3.456-3.973(m,36H),3.217-3.366(m,10H),2.092-2.712(m,22H),1.954-2.000(m,13H),1.307-1.718(m,43H),0.575-1.048(m,16H)；31PNMR(CD3OD,162MHz):δ0.709(P)。
实施例7、化合物003006int2的合成
化合物003006int1(20g，0.14mol)和Py(17g，0.2mol)在DMF(200mL)中滴入苯基碳酸氯酯(22g，0.14mmol)，在0℃下搅拌一夜，然后将上述溶液倒入冰水(500mL)中，用乙酸乙酯(200mL x3)萃取。结合的有机层用Na2SO4干燥，浓缩得到棕色固体化合物003006int2(25g，粗品)。LC/MS(ESI)m/z:[M+H]+264。
实施例8、化合物003006int3的合成
化合物003006int2(25g，0.13mmol)、TEA(13g，0.13mol)和环丙胺(15g，0.26mol)在DCM(300mL)中混合，室温下搅拌过夜。混合物用水冲洗，减压搅拌，得到棕色固体化合物006003int3(12g，57％)。LC/MS(ESI)m/z:[M+H]+227。
实施例9、化合物003006int4的合成
化合物003006int3(12g，52.9mmol)、K2CO3(13g，106mmol)和4-氯-7-甲氧基喹啉-6-羧酸甲酯(16g，63.5mol)加入DMF(120mL)中，在80℃搅拌过夜。将混合物倒入冰水中过滤，滤饼用水洗净，干燥后得到褐色固体化合物003006int4(14g，59.8％)。LC/MS(ESI)m/z:[M+H]+442。
实施例10、化合物003006int5的合成
化合物003006int4(14g，31.7mmol)和LiOH(2.5g，63.4mmol)在甲醇水溶液(140mL)中室温反应一夜。反应溶液加入1N盐酸调节PH至2-3，过滤得黄色固体化合物5(10g，73.5％)。LC/MS(ESI)m/z:[M+H]+428。
实施例11、化合物003006int6的合成
将化合物003006int5(1g，2.3mmol)和7-氨基庚酸乙酯(485mg，2.8mmol)在10mL的DCM溶液中加入反应液HOBT(474mg，3.5mmol)EDCI(672mg，3.5mmol)DIEA(755mg，5.8mmol)，在室温搅拌一夜，用DCM(10mL x 2)萃取。结合有机层在Na2SO4上干燥并浓缩，得到粗产物，经硅胶纯化得到黄色溶液化合物003006int6(700mg，51.5％)。LC/MS(ESI)m/z:[M+H]+583。
实施例12、化合物003006int7的合成
化合物003006int6(700mg，1.2mmol)和LiOH(96mg，2.4mmol)在甲醇水溶液(10mL)中反应过夜，加入1N盐酸调节PH至2-3，过滤得黄色固体化合物003006int7(300mg，45％)。LC/MS(ESI)m/z:[M+H]+555。
实施例13、化合物003006的合成
在化合物003006int7(300mg，0.54mmol)和7A(279mg，0.65mmol)的DCM(5mL)溶液中加入HOBT(110mg，0.81mmol)、EDCI(155mg，0.81mmol)和DIEA(175mg，1.3mmol)，然后在反应液中搅拌一夜，反应后用DCM(10mL×2)提取。结合的有机层在Na2SO4上干燥并浓缩，得到粗产物，用制备高效液相色谱法纯化，得到白色固体WGint4(003006)(120mg，22.9％)。LC/MS(ESI)m/z:[M+H]+967。
实施例14、化合物005000int2的合成
化合物005000int1(10g，0.11mol)，丙烯酸叔丁酯(18g，0.14mol)和叔丁醇钾(0.16g，1.4mmol)在THF(100mL)中溶解，室温搅拌过夜，用1N盐酸(50mL)淬火，用EA(50mL*2)萃取。结合的有机层在Na2SO4干燥并浓缩，得到化合物005000int2(20g，81.9％)，无需进一步纯化。LC/MS(ESI)m/z:[M+H]+223。
实施例15、化合物005000int3的合成
将化合物005000int3(10g，0.045mol)在100mL THF溶液中加入量为(2.6g，0.068mol)的edLAH溶液，在0℃下分三次加入。在室温下搅拌反应3h。反应被Na2SO4.10H2O抑制。对混合物进行过滤，滤液蒸发，得到化合物005000int3(6克，88.2％)。LC/MS(ESI)m/z:[M+H]+153。
实施例16、化合物005000int4的合成
化合物005000int3(6g，0.039mol)、丙烯酸叔丁酯(6.6g，0.052mol)和叔丁醇钾(0.22g，0.002mol)在THF(100mL)中搅拌过夜，用1N盐酸(50mL)淬火，用EA(30mL*2)萃取。结合有机层用Na2SO4干燥，浓缩得到化合物005000int4(10g，90.7％)，不需进一步纯化。LC/MS(ESI)m/z:[M+H]+281。
实施例17、化合物side1的合成
化合物005000int4(5g，0.018mmol)和碘化钠(13.5g，0.09mol)在丙酮(50mL)中，50℃下搅拌48h。冷却后，溶剂在真空中蒸发，用水洗涤(20mL*2)得到side1(5g，74.9％)。LC/MS(ESI)m/z:[M+H]+373。
实施例18、化合物005000int8的合成
化合物005000int7(10g，0.033mol)，005000int7A(5.6g，0.037mol)，DIEA(0.28g，0.01mol)在NMP(100mL)中，在130℃的条件下搅拌过夜。混合物用制备高效液相色谱法纯化，得到化合物005000int8(5g，35.7％)。LC/MS(ESI)m/z:[M+H]+421。
实施例19、化合物005000int9的合成
在化合物005000int8(4g，9.5mmol)和NH4Cl(10g，0.19mol)乙醇(20mL)和水(20mL的溶液中，加入Zn(10g，0.15mol)，在80℃下搅拌2h。反应物经过过滤蒸发，残渣用硅胶纯化，得到化合物005000int9(3.2g，86.5％)。LC/MS(ESI)m/z:[M+H]+391。
实施例20、化合物005000int10的合成
将化合物005000int9(3.9g，10mmol)、化合物9A(2.7g，12mmol)和TEA(1.5g，15mmol)在DMF(40mL)中加入HOBT(2g，15mmol)和EDCI(573mg，3mmol)。反应在室温下搅拌过夜，然后用Na2CO3水溶液进行淬火，用EA萃取，蒸发结合的有机层，硅胶纯化得到化合物005000int10(3g，50.4％)。LC/MS(ESI)m/z:[M+H]+596。
实施例21、化合物Core 1的合成
化合物005000int10(1.5g，7.2mmol)和Pd/C(200mg)在甲醇(20mL)中的溶液在H2气囊下室温搅拌一夜。反应过滤后蒸发得到化合物core 1(1g，78.7％)。LC/MS(ESI)m/z:[M+H]+506。
实施例22、化合物006000int11的合成
将化合物core 1(500mg，0.99mmol)、side 1(447mg，1.28mmol)和碳酸铯(980mg，3mmol)溶液在DMF(5mL)中30℃搅拌过夜。将反应液倒入水中，用EA(10mL×2)萃取。结合有机层用Na2SO4干燥后浓缩，得到粗产物，经硅胶纯化得到白色固体化合物006000int11(350mg，47.2％).LC/MS(ESI)m/z:[M+H]+750。
实施例23、化合物006000int12的合成
化合物006000int11(300mg，0.4mmol)溶液中加入TFA(0.3mL)。混合物室温下搅拌过夜。溶剂蒸发得到化合物006000int12(200mg，72.2％)。LC/MS(ESI)m/z:[M+H]+694。
实施例24、化合物WGint4(006000)的合成
化合物006000int12(100mg，0.14mmol)和12A(75mg，0.17mmol)在1mL的DCM中加入HOBT(30mg，0.22mmol)，EDCI(43mg，0.22mmol)和DIEA(65mg，0.5mmol)。混合物室温下搅拌过夜。反应物加入水中，用DCM(10mL×2)提取。结合的有机层用Na2SO4干燥并浓缩，得到粗产物，用制备高效液相色谱法纯化，得到白色固体WGint4(006000)(20mg，13％)。LC/MS(ESI)m/z:[M+H]+1106。
实施例25、化合物005000int13的合成
将化合物core 2(600mg，1.23mmol)、化合物side 1(584mg，1.57mmol)和碳酸铯(980mg，3mmol)溶液在DMF(5mL)中在30℃搅拌过夜。将反应液倒入水中，用EA(10mL×2)萃取。结合有机层用Na2SO4干燥并浓缩，得到粗产物，经硅胶纯化得到白色固体化合物005000int13(200mg，22.2％)。LC/MS(ESI)m/z:[M+H]+732。
实施例26、化合物005000int14的合成
化合物005000int13(300mg，0.4mmol)溶液中加入TFA(0.3mL)。混合物在室温下搅拌过夜。溶剂蒸发得到化合物005000int14(200mg，72.2％)。LC/MS(ESI)m/z:[M+H]+676。
实施例27、化合物WGint4(005000)的合成
化合物005000int14(100mg，0.14mmol)和14A(75mg，0.17mmol)在1mL的DCM中加入加入HOBT(30mg，0.22mmol)，EDCI(43mg，0.22mmol)和DIEA(65mg，0.5mmol)。混合物室温下搅拌过夜。反应物加入水中，用DCM(10mL×2)提取。结合的有机层用Na2SO4干燥并浓缩，得到粗产物，用制备高效液相色谱法纯化，得到白色固体WGint4(005000)(16mg，8％)。LC/MS(ESI)m/z:[M+H]+1088。
实施例28、WG-2–WG-25化合物的合成
采用上述实施例1-27的相同或类似方法，进而合成了化合物WG-2–WG-25，其LC/MS的结构确证数据如下表所示：
表1.WG-2–WG-25化合物的结构确证数据
实施例29、溶解度测试
按照计划配制浓度分别为1nM/10nM/100nM/1uM/10uM/100uM/1mM系列的溶液，分别称取一定质量的本专利的待测WG化合物和对应的A化合物，使用去离子水配制，置37℃恒温条件下振荡12小时至溶解平衡。用滤膜过滤3次，取滤液。使用HPLC测定化合物在溶液中的实际浓度，并绘制溶液实际浓度-计划配制溶液浓度曲线，得到的曲线转折点即为该化合物的平衡溶解度。
分析计算WG化合物的溶解度与对应的A结构化合物的溶解度的变化。
实施例30、跨膜性测试
取肝癌细胞(本专利中使用HUH-7)以4*105个细胞/mL的浓度接种到6孔板中，每孔2mL，孵育过夜等待细胞贴壁。
隔天进行化合物配置，分别称取一定量本专利的WG化合物和对应的A化合物，先用纯DMSO配置成浓度较高的母液，采取梯度稀释的方法，配置出溶剂为含10％DMSO的化合物浓度为10uM/30uM/100uM/150uM/300uM药液，震荡使其充分混匀。
使用显微镜观察确认细胞贴壁后，每孔按照药液比培养基1:10的比例加入200uL药液。
孵育24小时后取出细胞，用移液枪将培养基吸出，再使用磷酸缓冲液清洗，每次加入2mL，持续30s，重复五次，使细胞外环境不再残留药物。将孔板内的液体彻底吸干，每孔加入150uLRIPA裂解液，在冰上孵育30min将细胞裂解。
收集裂解液，在100000rpm下离心1h后取出上清，使用HPLC测定上清中化合物的浓度。
分析计算WG化合物的溶解度与对应的A结构化合物的跨膜性的变化，取不同浓度下跨膜效率变化的算术平均值，得到两组化合物跨膜效率差异的参考值。
实施例31、细胞生长抑制测试
取肝癌细胞(本专利使用HUH-7)以2*104个细胞/mL的浓度接种到96孔板中，每孔加入100uL。孵育过夜。
隔天用显微镜观查细胞确认贴壁。配置化合物，分别称取一定量本专利的WG化合物和对应的A化合物，先用纯DMSO配置成浓度较高的母液，采取梯度稀释的方法，配置出溶剂为含10％DMSO的化合物浓度为10nM/100nM/300nM/1000nM/3000nM药液，震荡使其充分混匀。
对照组采用同样的溶剂和方式配置阳性药的药液，只需一个剂量即可，本实验中选用乐伐替尼1uM。
配置好后在96孔板中每孔加入10uL药液，每个剂量重复三次。轻轻摇晃使细胞和药液重复接触，放入培养箱中孵育72个小时。72小时后取出，用cck-8试剂盒显色，每孔加入10uL cck-8试剂，轻轻摇匀后在培养箱中孵育两小时。两小时后取出，使用酶标仪在450nm波长下测量每孔的吸光度，根据公式：细胞生长抑制率＝[1-(实验组吸光度-培养基对照组吸光度)/(空白对照组吸光度-培养基对照组吸光度)]×100％，可得到化合物在当前剂量和时间下对肝癌细胞的生长抑制能力。依照浓度的梯度绘制图表，可直观的对照结果。
实施例32、蛋白降解测试
取肝癌细胞(本专利为HUH-7)以4*105个细胞/mL的浓度接种到6孔板中，每孔2mL，孵育过夜等待细胞贴壁。
隔天进行化合物配置，分别称取一定量本专利的WG化合物和对应的A化合物，先用纯DMSO配置成浓度较高的母液，采取梯度稀释的方法，配置出溶剂为含10％DMSO的化合物浓度为10nM/30nM/100nM/300nM/1000nM/3000nM的药液，震荡使其充分混匀。每孔按照药液比培养基1:10的比例加入200uL药液。
孵育24小时后取出细胞，用移液枪将培养基吸出，再使用PBS清洗3次。将孔板内的液体彻底吸干，每孔加入150uLRIPA裂解液，在冰上孵育30min将细胞裂解。
收集裂解液，在16000rpm下离心10分钟，取上清，用BCA试剂盒调平总蛋白含量后，用Western blot方法检测目标蛋白含量。
用ImageJ分析结果，测量各个条带的黑度，按照蛋白量＝实验组黑度值/空白对照组黑度值，将蛋白量化，比较分析。
依据实施例29-实施例32的方法，我们进行了五个化合物的对照测试：
以WGint4(003006)/WG-1(00300639)为例，其中WGint4(003006)为WG-1(00300639)所对应的A结构化合物。
(1)溶解度(平衡溶解度)
WGint4(003006)溶解度为31uM，WG-1(00300639)溶解度为677uM，溶解度约增强22倍。
(2)跨膜性
如图5所示，由其数据可得出，WG-1(00300639)的跨膜效率约为WGint4(003006)的9.2倍。
(3)癌细胞生长抑制效果
从图6可以看出，WG-1(00300639)对肝癌细胞的生长抑制明显强于WGint4(003006)。计算得WG-1(00300639)IC50＝21.3nM，WGint4(003006)IC50＝210.7nM。
(4)蛋白降解
结果如图7所示，测试数值如下表所示：
计算得WG-1(00300639)DC50＝18.0nM，WGint4(003006)DC50＝150.2nM。
其他化合物具体数据如下：
应该理解，本发明描述的具体实例和方案仅仅是为了例证目的作为示例给出，不视为对本发明的限制，包括在本申请的精神和范围内的各种进一步修改或变化均视为涵盖在本发明的公开范围内。
Claims (15)
1.一种具有如下结构的化合物或其药学上可接受的盐、立体异构体、溶剂化物或多晶型物，所述化合物由以下三部分组成：
A-BD-CON
其中CON为去唾液酸糖蛋白受体(ASGPR)的配体,
A为LGP-Y-Z-LK-LGE的结构,
其中，LGP为靶蛋白结合配体，LGE为E3泛素连接酶配体；
Y，Z分别独立地是共价键，CH2，C1-C4烷基取代的亚甲基，NH，C1-C4烷基取代的氮原子，O或者S；当Y选自O，S，NH或C1-C4烷基取代的氮原子时，Z选自共价键，CH2，C1-C4烷基取代的亚甲基；当Z选自O，S，NH或C1-C4烷基取代的氮原子时，Y选自共价键，CH2，C1-C4烷基取代的亚甲基；
LK一端通过Y-Z与LGP连接，另一端通过共价键与LGE连接，LK特征为选自如下结构单元：
其中m任选为0-5的自然数；n任选为0-20的自然数；p任选为0-4的自然数；q任选为0-20的自然数；r任选为1-3的自然数；s任选为1-5的自然数；
X任选是CH2、O，S,NR1，R1任选为H、C1-6烷基、C1-6卤代烷基或者C1-6烷氧基取代的C1-6烷基；
BD为A与CON的连接物，特征为具有Q-LN的结构；其中Q在细胞内的内体或溶酶体内水解酶酸性条件下可以降解断裂，释放A；Q的结构包括腙、脲，肟、二硫基、硫醚、酰胺、酯(羧酸酯、磷酸酯、焦磷酸酯、碳酸酯、硫酸酯、磺酸酯、氨基磺酸酯、亚甲基磺酸酯、氨基甲酸酯)、
LN为Q与CON之间的连接基团，选自3-20个碳原子的碳链，其中任意的CH2可被O、NH、C(O)取代。
2.权利要求1所述的化合物，其特征在于所述的LGE为泛素化E3酶的配体，优选为VonHippel–Lindau肿瘤抑制因子(Von Hippel–Lindau tumor suppressor,pVHL)的配体；进一步优选为如下通式表达的结构，
分子两端分别与LK和Q结构单元相连，LK与Q的定义与权利要求1项相同；G为C1-C10烷基，C3-C10环烷基，3-10元含有1-3个O、N、S原子的杂环烷基，优选异丙基，叔丁基，环己基或四氢吡喃；更优选叔丁基。
3.根据权利要求1或2所述的化合物，其结构可由如下通式表示：
其中通式中Q选自如下结构单元：
通式中LN选自如下结构单元
其中V任选为自然数3-15；V优选的为自然数5-12，
通式中G为C1-C10烷基，C3-C10环烷基，3-10元含有1-3个O、N、S原子的杂环烷基，优选异丙基，叔丁基，环己基或四氢吡喃；更优选叔丁基，
通式中Y，Z与权利要求1中Y，Z相同，
通式中LK独立地选自与权利要求1中LK相同的结构单元。
4.权利要求1-3所述的化合物，其特征在于CON结构特征表示如下：
其中S1-S3分别独立地选自如下结构单元：半乳糖、半乳糖胺、葡萄糖、葡萄糖胺、甘露糖、甘露糖胺、乳糖酸；其中包括D构型或L构型糖结构；
其中S1-S3通过阿尔法糖苷键或者贝塔糖苷键分别与L1-L3连接；
其中L1-L3分别独立地选自如下结构：化学键，C3-C15长度的脂肪碳链，C3-C15长度的在中间任意位置插入一个或多个O，S、NH或羰基的脂肪碳链；
其中M选自C，N，O，S，P(＝O)并与LN通过共价键连接；
其中S1-L1，S2-L2，或S3-L3可以分别独立地不存在。
5.权利要求1-3任一项所述的化合物，其特征在于所述CON选自以下的结构：
6.权利要求1-3所述的化合物，其特征在于LGP选自如下结构单元：
其中R2-R5分别独立选自H，F，Cl，Br，C1-4烷基、C1-4烷氧基；R6选自H，C1-4烷基、C1-4烷氧基。
7.权利要求1-3，6任一项所述的化合物，其特征在于所述LGP为癌症相关靶点、微生物相关靶点、免疫疾病相关靶点、神经退行性疾病相关靶点、代谢类疾病相关靶点的配体。
8.权利要求6所述的化合物，其特征在于LGP结合的靶点为激酶、转录因子、表观遗传阅读窗、微管相关蛋白、微生物相关蛋白等。
9.权利要求6所述的化合物，其特征在于LGP结合的靶点为EGFR、VEGFR、FGFR、PDGFR、Raf、Braf、RET、FLT、c-Kit、MET、ACVR、ALK、AKT、AhR、AURKA、AR、RAR、ER、BCL、BCR-ABL、BET、BMPR、BLK、BTK、BRD、CDK、CK、CHEK1、CTNNB1、DDR、DHODH、RAS、EED、ESR1、CRABP、CRBN、HER2、HER3、HMGCR、Htt、GNA11、GNA1、GNAS、NQO、TROP、eIF4E、ERK、ERG、ETV、ERRα、EZH2、FAK、IDH1/2、IGF1R、IRAK4、JAK、MEK、MELK、LTK、FKBP、MDM2、HDAC、MER、MCL、MTOR、PAR、PBRM、PCAF、PDE、PD-1、PD-L1、PTK、PARP、PDXK、PLK、PKB、MAPK、PI3K、Pirin、RIPK、Rpn13、PRC、P38、TGFβ、AFP、NTRK、NHE、CEA、SOAT1、SNCA、SYK、RNF43、DLK1、gp96、SGK、SMAD、SMO、SFB、SHP、SIK、SRC、STAT3、TBK、TYK3、TRIM、NS3、IRAK4、PCAF、GCN5、Sirt2、Tau、TUB、Wee1、ZAK或者其组合靶点。
10.权利要求6所述的化合物，其特征在于所述LGP为Hsp90抑制剂、激酶抑制剂、磷酸酶抑制剂、MDM2抑制剂、靶向含有人BET布罗莫结构域的蛋白的化合物、HDAC抑制剂、人赖氨酸甲基转移酶抑制剂、靶向RAF受体的化合物、靶向FKBP的化合物、血管生成抑制剂、免疫抑制性化合物、靶向芳基烃受体的化合物、靶向雄激素受体的化合物、靶向雌激素受体的化合物、靶向甲状腺激素受体的化合物、靶向HIV蛋白酶的化合物、靶向HIV整合酶的化合物、靶向HCV蛋白酶的化合物、靶向酰基蛋白硫酯酶1和/或2的化合物。
11.权利要求9所述的化合物，其特征在于所述LGP为：索拉非尼、乐伐替尼、瑞格非尼、卡博替尼、阿帕替尼、法瑞替尼、卡铂、顺铂、奥沙利铂、依维莫司、培美曲塞、厄洛替尼、达沙替尼、伊马替尼、舒尼替尼、奥西替尼、依布替尼、阿来替尼、克唑替尼、恩曲替尼、阿法替尼、阿西替尼、色瑞替尼、拉罗替尼、布加替尼、来那替尼、曲美替尼、拉帕替尼、纳拉替尼、5-氟尿嘧啶、依托泊苷、吉西他滨、地西他滨、卡培他滨、多柔比星、表柔比星、长春新碱、替莫唑胺、长春新碱、异环磷酰胺、米托蒽醌、吉非替尼、硼替佐米、紫杉醇、多西他赛、聚乙二醇化干扰素α-2a、干扰素α-2a、聚乙二醇化干扰素α-2b、干扰素α-2b、阿扎胞苷、阿糖胞苷、环胞苷、伊立替康、拓扑替康、阿糖腺苷、碘苷(IDU)、三氟胸苷、溴乙烯去氧尿苷、甘草酸镁、甘草酸苷、谷胱甘肽、多磷脂酰胆碱、腺苷蛋氨酸、熊去氧胆酸、乌司他丁。
12.权利要求1-11任一项所述的化合物，其特征在于，代表性化合物具有以下的结构：
优选地，所述化合物具有WG-1、WG-2、WG-3、WG-4、WG-5、WG-6所示的结构。
13.包含权利要求1-12任一项所述化合物的药物组合物。
14.权利要求1-12任一项所述化合物及权利要求13所述组合物在制备治疗肿瘤药物中的应用，优选地所述肿瘤为肝癌。
15.权利要求1-12任一项所述化合物及权利要求13所述组合物在制备治疗肝部疾病药物中的应用，优选地所述肝部疾病为肝炎。
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| CN115215799B (zh) * | 2022-08-12 | 2024-05-31 | 上海爱博医药科技有限公司 | 脲类多靶点酪氨酸激酶抑制剂及其多种医药应用 |
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| CN117599199A (zh) * | 2023-11-20 | 2024-02-27 | 北京大学 | 用于靶蛋白水解的聚合物及其制备方法和用途 |
| CN117736187A (zh) * | 2024-02-19 | 2024-03-22 | 天津匠新致成科技有限公司 | 一种蛋白水解靶向嵌合体及其制备方法、药物组合物和应用 |
| CN117736187B (zh) * | 2024-02-19 | 2024-04-30 | 天津匠新致成科技有限公司 | 一种蛋白水解靶向嵌合体及其制备方法、药物组合物和应用 |
Also Published As
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| WO2021219077A1 (zh) | 2021-11-04 |
| CN113563414B (zh) | 2022-08-12 |
| US20240270780A1 (en) | 2024-08-15 |
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