CN111018857A - 靶向蛋白酶降解平台(ted) - Google Patents
靶向蛋白酶降解平台(ted) Download PDFInfo
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- CN111018857A CN111018857A CN201811174965.7A CN201811174965A CN111018857A CN 111018857 A CN111018857 A CN 111018857A CN 201811174965 A CN201811174965 A CN 201811174965A CN 111018857 A CN111018857 A CN 111018857A
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Classifications
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Abstract
本发明涉及靶向蛋白酶降解平台(TED),具体地,本发明公开了一种式I所示的靶标分子‑连接体‑E3连接酶配体的偶联物,A‑L1‑B(式I),其中,所述A为靶标分子的一价基团;所述B为E3连接酶配体的一价基团;所述L1为连接A和B的连接头;且L1如下式II所示:‑X‑L2‑Y‑(式II)。
Description
技术领域
本发明属于生物医药,具体地,涉及一种靶向蛋白酶降解平台(TED)。
背景技术
现代分子生物学从3个基本层次上调控蛋白的表达水平:首先,在DNA水平,通过基因敲除,从而使目标蛋白的DNA失活;其次,在mRNA水平,通过小分子RNA,与目标蛋白的mRNA结合,从而抑制mRNA的翻译及表达;再次,在蛋白水平,通过对翻译后靶蛋白的修饰,例如甲基化、磷酸化、糖基化等,从而调整靶蛋白的量及活性。
就药物研发的总体发展来看,小分子和大分子两种药物形式都有各自的优势与不足。如小分子药物的发展一直面临如何维持体内药物浓度以及耐药性等关键挑战。有些靶点部位的形状不利于小分子的药物设计而成为“不可成药”的靶点。针对这些靶点目前还未找到有效的调控方式。单抗虽相对于小分子具有高亲和力和高选择性的优势,易于开发成高效、高选择性的药物,但其最大的弊端在于无法透过细胞膜,因此无法作用于胞内靶点。抗体药物偶联体(ADC)利用具有内吞性的抗体提供靶向并作为载体将超级毒素药物送达靶向部位。ADC类药物开发遇到的瓶颈是治疗窗口不够宽,除了抗体本身引起的毒副作用外,超级毒素会因偶联的非均一性而在到达靶位前脱落,引起严重毒副作用。此外,泛素-蛋白酶体系统正常生理功能负责清理细胞中变性、变异或者有害的蛋白。
综上所述,本领域迫切需要开发能够更高效、且可重复利用的降解靶蛋白从而治疗相关疾病的化合物。
发明内容
本发明的目的在于提供一种能够更高效、且可重复利用的降解靶蛋白从而治疗相关疾病的化合物。
在本发明的第一方面,提供了一种式I所示的偶联物:
A-L1-B 式I
其中:
所述A为靶标分子的一价基团;
所述B为E3连接酶配体的一价基团;
所述L1为连接A和B的连接头;且L1如下式II所示:
-X-L2-Y- 式II
其中,
当X或Y为NH或NR时,X或Y与和它们相连的L2链中的一部分共同形成4-8元芳香或非芳香杂环;其中,R为取代或未取代的C1-C10烷基、-(C=O)-R’、(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’或-NH-CO-NH-R’、-NH-CO-O-R’或-X’-L3-Z;其中L3为连接基团,而Z为多肽元件或者靶标分子T;其中,R’选自下组的基团:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、氨基保护基、或者-X’-L3-Z;
或
X和Y各自独立地选自下组:-O-、-S-、-NH-、-NR-、-(C=O)NH-、-NH(C=O)-、-SO2-、-NHSO2-、-SO2NH-、-SO-、-NHSO-、-SONH-、-PO3-、-NHCOO-、-COO-、-NHCOCH2O-、或-NH-CO-NH-;其中,R为取代或未取代的C1-C10烷基、-(C=O)-R’、-(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’或-NH-CO-NH-R’、或-X’-L3-Z;;
其中,L3为连接基团,而Z为多肽元件或者靶标分子T;其中,R’选自下组的基团:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、保护基、或者-X’-L3-Z;
X’选自下组:-O-、-S-、-NH-、-(C=O)NH-、-NH(C=O)-、-SO2-、-NHSO2-、-SO2NH-、-SO-、-NHSO-、-SONH-、-PO3-、-NHCOO-、-COO-、-COOCH2-或-NH-CO-NH-;
L2和L3各自独立地为选自下组的连接基团:
(a)取代或未取代的5-20元碳链;
(b)取代或未取代的含有1-5个选自N、O和S的杂原子的5-20元杂碳链;
(c)取代或未取代的5-20元碳链,且链中的1-4个链原子被选自下组的杂环替换:含有1-4个选自N、O和S的杂原子的4-10元饱和杂环、含有1-4个选自N、O和S的杂原子的5-10元部分不饱和或完全不饱和杂环;
(d)取代或未取代的含有1-5个选自N、O和S的杂原子的5-20元杂碳链,且链中的1-4个链原子被选自下组的杂环替换:含有1-4个选自N、O和S的杂原子的4-10元饱和杂环、含有1-4个选自N、O和S的杂原子的5-10元部分不饱和或完全不饱和杂环;
其中,所述“取代”指基团上的一个或多个(优选为1、2、3、或4个)氢原子被选自下组的取代基所取代:C1-C10烷基、C3-C8环烷基、-COOH、-OH、-SH、-NH2、-NHR、-N(R1)R2、-Z、-X’-L3-Z、 其中,Z为多肽元件或者靶标分子T;其中,当取代基为-Z时,则-Z仅仅位于N原子上;其中,R1和R2各自独立地为H、C1-C6烷基、C3-C8环烷基、氨基保护基、-X’-L3-Z
其中,R为取代或未取代的C1-C10烷基、-(C=O)-R’、(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’或-NH-CO-NH-R’、-NH-CO-O-R’或-X’-L3-Z;;其中L3为连接基团,而Z为多肽元件或者靶标分子T;其中,R’选自下组的基团:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、保护基、或者X’-L3-Z。
在另一优选例中,R1和R2不同时为-X’-L3-Z
在另一优选例中,所述的多肽元件选自下组:配体或其活性片段、受体或其活性片段、抗体或其活性片段、或其组合。
在另一优选例中,所述的Z选自下组:配体、可溶性受体、抗体、或抗体-药物偶联物(ADC)、或其组合。
在另一优选例中,所述的靶标分子T与靶标分子A是相同的或不同的。
在另一优选例中,所述的靶标分子T与靶标分子A各自独立地选自下组:叶酸、HSP90抑制剂、或其组合。
在另一优选例中,所述的配体包括全长的配体或其活性片段。
在另一优选例中,所述的抗体包括全长的抗体或其活性片段。
在另一优选例中,所述的抗体包括单链抗体或双链抗体。
在另一优选例中,所述含有1-4个选自N、O和S的杂原子的4-10元饱和杂环可以是单环、双环或三环。
在另一优选例中,所述含有1-4个选自N、O和S的杂原子的4-10元饱和杂环可以是并环或螺环。
在另一优选例中,所述含有1-4个选自N、O和S的杂原子的4-10元饱和杂环可以是含有1个氮原子的4-6元饱和环或含有1个氮原子的4-6元饱和环。
在另一优选例中,所述含有1-4个选自N、O和S的杂原子的5-10元部分不饱和或完全不饱和杂环可以是单环、双环或三环。
在另一优选例中,所述含有1-4个选自N、O和S的杂原子的5-10元部分不饱和或完全不饱和杂环可以是并环或螺环。
在另一优选例中,所述含有1-4个选自N、O和S的杂原子的5-10元部分不饱和或完全不饱和杂环可以是含有1-4个选自N、O和S的杂原子的五元部分不饱和或完全不饱和杂环。
在另一优选例中,L2和/或L3为选自下组的连接基团:
(a)取代或未取代的-(CH2)s-;
(b)取代或未取代的-(CH2)s-,其中,1-5个-CH2-被O替换;
(c)取代或未取代的-(CH2)s-,其中,1-2个-CH2-被NR替换和任选地1-2个-CH2-被O替换;其中,R为H、保护基或X’-L3-Z;
(d)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被含有1-4个选自N、O、S和P的杂原子的五元不饱和杂环替换;
(e)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被含有1-4个选自N、O、S和P的杂原子的4-6元饱和杂环替换;
(f)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被O和含有1-4个选自N、O、S和P的杂原子的4-6元饱和杂环替换;
(g)二价的含有1-2个氮原子的4-6元杂环基团;
其中,s为5-20的整数。
在另一优选例中,s为3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
在另一优选例中,所述的取代的-(CH2)s-指被一个或多个选自下组的基团所取代:C1-C10烷基、C3-C8环烷基、-NH2、-NHR、-NR1R2,其中,R1和R2各自独立地为H、C1-C6烷基、C3-C8环烷基、保护基、或R,其中R的定义如上,且R1和R2不同时为多肽元件或者靶标分子T。
在另一优选例中,所述的L2和/或L3选自下组:
(d1)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被含有1-3个选自N、O、S和P的杂原子的五元不饱和杂环替换;
(e1)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被含有1-3个选自N、O、S和P的杂原子的4-6元饱和杂环替换;
(f1)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被O和含有1-3个选自N、O、S和P的杂原子的4-6元饱和杂环替换。
在另一优选例中,所述的L2和/或L3选自下组:
(d2)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被含有1-2个N原子的五元不饱和杂环替换;
(e2)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被含有1-2个N原子的4-6元饱和杂环替换;
(f2)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被O和含有1-2个N原子的4-6元饱和杂环替换。
在另一优选例中,s为5-15,较佳地6-10。
在另一优选例中,当X为NH或NR时,X与和它相连的L2链中的一部分共同形成4-8元杂环,
其中,Y和R如上定义;m为1-15的整数;p和q各自独立地为0、1、2或3,且p+q≥2。
在另一优选例中,L1选自下组:
其中,
X和Y如上定义;
p和q各自独立地为1、2或3的整数。
在另一优选例中,L1为选自下组的基团失去两个任意位置上的氢原子形成的二价连接基团:
式中,p和q如上定义。
在另一优选例中,L1选自下组:
式中,“Y,X”表示该末端为X或Y;附加条件是一端为X,而另一端为Y;
X和Y如上定义,m和n各自独立地为0-15的整数;
T、V、Q、和W各自独立地为CH、C=O、S、O、NH或NR;R为C1-C10烷基、-(C=O)NH-、-(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’、-NH-CO-NH-R’、-NH-CO-O-R’、或N-'X'-L3-Z(即-X'-L3-Z为位于N上的取代基);其中L3的定义如上文中所述,而Z为多肽元件或者靶标分子T;R’如上定义。
在另一优选例中,T、V、Q、和W中至少一个为N-'X'-L3-Z。
在另一优选例中,m+n≤20。
在另一优选例中,m+n≥2。
在另一优选例中,L1选自下组:
各式中,X和Y如上定义,m和n各自独立地为0-15的整数;
R为X’-L3-Z,且L3和Z如上定义;
Q和W各自独立地为CH、C=O、S、O、NH或NR”’;R”’为-(C=O)-R’、(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’、-NH-CO-NH-R’或-NH-CO-O-R’;R’如上定义。
在另一优选例中,Z为选自抗体、受体、配体、或它们的活性片段的多肽元件。
在另一优选例中,Z为ADC。
在另一优选例中,m+n≤20。
在另一优选例中,m+n≥2。
在另一优选例中,L1为
其中,X、Y和R如上定义;
m和n各自独立地为1-15的整数;p为1、2或3。
在另一优选例中,L1选自下组:
各式中,X、Y如上定义;m为1-15的整数;p为1、2或3。
在另一优选例中,所述连接体选自下组:
式中,X、Y的定义如上,m和n各自独立地为0-15的整数。
在另一优选例中,m+n≤20。
在另一优选例中,m+n≥2。
在另一优选例中,所述的L1选自下组:
其中,R1和R2各自独立地为H、C1-C6烷基、C3-C8环烷基、保护基、或R,其中R的定义如上,且R1和R2不同时为多肽元件。
在另一优选例中,所述L1为选自下组的基团失去两个任意位置上的氢原子形成的二价连接基团:
在另一优选例中,所述靶标分子A和T各自独立地选自下组:叶酸、HSP90、TINFRm、TNFR2、NADPH氧化酶(oxidase)、BclIBax、C5a受体(receptor),HMG-CoA还原酶(reductase)、PDE I-V、角鲨烯环化酶抑制剂(Squalene cyclase inhibitors)、CXCR1、CXCR2、一氧化氮(NO)合成酶(Nitric oxide(NO)synthase)、环加氧酶(cyclo-oxygenase)1-2、5HT受体(5HT receptors)、多巴胺受体(dopamine receptors)、G-蛋白(G-proteins)、Gq、组胺受体(Histamine receptors)、脂肪氧合酶(Lipoxygenases)、类胰蛋白酶丝氨酸蛋白酶(Tryptase serine protease)、胸苷酸合成酶(Thymidylate synthase)、嘌呤核苷酸磷酸化酶(Purine nucleotide phosphorylase)、GAPDH锥虫(GAPDH trypanosomal)、糖原磷酸化酶(Glycogen phosphorylase)、碳酸酐酶(Carbonic anhydrase)、趋化因子受体(Chemokine receptors)、JAW STAT、RXR及其类似物、HIV 1蛋白酶(HIV 1 protease)、HIV1整合酶(HIV 1integrase)、流感(Influenza)、乙型肝炎逆转录酶(hepatitis B reversetranscriptase)、神经氨酸酶(neuraminidase)、钠通道(Sodiumchannel)、MDR、蛋白质P-糖蛋白(protein P-glycoprotein)、酪氨酸激酶(Tyrosine kinases)、CD23、CD124、TKp56lck、CD4、CD5、IL-1受体(IL-1receptor)、IL-2受体(IL-2receptor)、TNF-aR,ICAM1,Ca+通道(Ca+channels)、VCAM、VLA-4整合素(VLA-4integrin)、VLA-4整合素(VLA-4integrin)、选择素(Selectins)、CD40/40L、新霉素和受体(Newokinins and receptors)、肌苷一磷酸脱氢酶(Inosine monophosphate dehydrogenase)、p38MAP激酶(p38MAP kinase)、白细胞介素-1转化酶(Interleukin-1converting enzyme)、胱天蛋白酶(Caspase)、HCV NS3蛋白酶(HCV NS3protease)、HCV-NS3RNA解旋酶(HCV-NS3RNA helicase)、甘氨酰胺核糖核苷酸甲酰转移酶(Glycinamide ribonucleotide formyl transferase)、鼻病毒3C蛋白酶(rhinovirus 3C protease)、HSV-I、CMV、ADP聚合酶(ADP-polymerae)、CDK、VEGF、催产素受体(oxytoxin receptor)、msomal转移蛋白抑制剂(msomal transfer proteininhibitor)、胆汁酸转移蛋白抑制剂(Bile acid transfer protein inhibitor)、5-a还原酶(5-a reductase)、血管紧张素11(Angiotensin 11),甘氨酸受体(Glycine receptors)、去甲肾上腺素再摄取受体(noradrenaline reuptake receptor)、内皮素受体(Endothelinreceptors)、神经肽Y和受体(Neuropeptide Y and receptors)、雌激素受体(Estrogenreceptors)、AMP、AMP脱氨酶(AMP deaminase)、ACC、EGFR、法呢基转移酶(Farnesyltransferase)。
在另一优选例中,所述多肽元件为抗体;优选地,所述抗体包括纳米抗体(nanobody)和/或小分子抗体(minibody)。
在另一优选例中,所述抗体可与选自下组的抗原或受体结合:DLL3、EDAR、CLL1、BMPR1B、E16、STEAP1、0772P、MPF、5T4,NaPi2b、Sema5b、PSCA hlg、ETBR、MSG783、STEAP2、TrpM4、CRIPTO、CD21、CD22、CD79b、CD19、CD37、CD138、FcRH2、B7-H4、HER2、NCA、MDP、IL20Rα、短小蛋白聚(Brevican)、EphB2R、ASLG659、PSCA、GEDA、BAFF-R、CD79a、CXCR5、HLA-DOB、P2X5、CD72、LY64、FcRH1、IRTA2、TENB2、PMEL17、TMEFF1、GDNF-Ra1、Ly6E、TMEM46、Ly6G6D、LGR5、RET、LY6K、GPR19、GPR54、ASPHD1、酪氨酸酶(Tyrosinase)、TMEM118、GPR172A、MUC1、CD70、CD71、MUC16、methothelin、FOLR1、Trop-2、gpNMB、EGFR、ENPP3、PSMA、CA6、GPC-3、PTK7、CD44、CD56、TIM-1、钙粘素-6(Cadherin-6)、ASG-15ME、ASG-22ME、CanAg、AXL、CEACAM5、EphA4、cMet、FGFR2、FGFR3、CD123、Her3、LAMP1、LRRC15、TDGF1、CD66、CD25、BCMA、GCC、Noch3和CD33。
在另一优选例中,所述E3连接酶配体选自下组:WO2017/176957 A1中的A1基团(例如A-10、A-11、A-15、A-28、A-48、A-69、A-85、A-93、A-98、A-99或A-101):
各式中,虚线表示与其他部分连接的位置(即与-L1-A连接的位置);
其中,Rx选自下组:NH、NH-CO、O、S、SO、SO2、SO2(NH2)NH、C1~C4亚烷基、C2~C5亚烯基、C2~C5亚炔基;Ry为C=O,C=S或CH2。
本发明的第二方面提供了一种药物组合物,其中,所述的药物组合物含有如第一方面所述的偶联物和药学上可接受的载体。
本发明的第三方面提供了如第一方面所述的偶联物的制备方法,其中,所述方法的反应路线如下式所示:
其中m,n的定义如上所述。
本发明的第四方面提供了如第一方面所述的偶联物的用途,用于制备用于治疗与靶标蛋白过量相关的疾病的药物组合物。
本发明的第五方面提供了一种减少细胞中靶标蛋白含量的方法,其中,将细胞与如第一方面所述的偶联物相接触,从而减少细胞中靶标蛋白的含量。
在另一优选例中,所述的方法是体外方法。
在另一优选例中,所述的方法是非诊断性和非治疗性的。
本发明的第六方面提供了一种减少对象中靶标蛋白含量或治疗与与靶标蛋白过量相关的疾病,其中,包括步骤:给需要的对象施用如第一方面所述的偶联物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1为靶向蛋白酶降解平台(TED)降解靶蛋白的作用原理示意图。
图2为实施例中偶联物生物测试结果。
具体实施方式
本发明人经过广泛而深入的研究,首次开发了一种结构新颖的TED偶联物,本发明偶联物具有式I所示的结构。此外,本发明偶联物非常适合进一步与多肽元件(尤其是抗体、蛋白配体)等进一步连接,从而使得本发明偶联物具有优异的双重靶向性,提高药物选择性,对致病蛋白实施更精准降解,减少非特异性降解可能引起的周身毒性,并有可能克服药物吸收代谢遇到的困难,铲除产生耐药性的机会。在此基础上完成了本发明。
术语
如本文所用,术语“本发明化合物”、“本发明偶联物”、“本发明的TED偶联物”可互换使用,指本发明第一方面中所述的式I化合物或偶联物。
如本文所用,除非另有定义,术语“烷基”本身或作为另一取代基的一部分是指具有指定碳原子数的直链或支链烃基(即,C1-8表示1-8个碳)。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。术语“烯基”指具有一个或多个双键的不饱和烷基。类似地,术语“炔基”指具有一个或多个三键的不饱和烷基。此类不饱和烷基的例子包括乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基和更高级的同系物和异构体。术语“环烷基”是指具有指定环原子数(例如,C3-6环烷基)并且完全饱和的或在环顶之间具有不超过一个双键的烃环。“环烷基”也指双环和多环烃环,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。术语“杂环烷基”是指含有一至五个选自N、O和S的杂原子的环烷基,其中氮和硫原子任选被氧化,且氮原子任选被季铵化。杂环烷基可以是单环、双环或多环体系。杂环烷基的非限制性例子包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、苯邻二甲酰亚胺、哌啶、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。杂环烷基可以经环碳或杂原子连接于分子的其余部分。对于诸如环烷基烷基和杂环烷基烷基的术语,是指环烷基或杂环烷基通过烷基或亚烷基连接体连接到分子的其余部分。例如,环丁基甲基-是连接到分子其余部分的亚甲基连接基上的环丁基环。
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷烃的二价基团,例如-CH2CH2CH2CH2-。烷基(或亚烷基)通常具有1-24个碳原子,其中本发明优选具有10个或更少碳原子的那些基团。“低级烷基”或“低级亚烷基”是较短链烷基或亚烷基,通常具有4个或更少的碳原子。类似地,“亚烯基”或“亚炔基”分别指具有双键或三键的不饱和形式的“亚烷基”。
除非另有说明,术语“杂烷基”本身或与其它术语组合是指的稳定的直链或支链或环状烃基或其组合,由指定数目的碳原子和和1至3个选自O,N,Si和S的杂原子组成,且其中氮和硫原子可选地被氧化,氮杂原子可任选地被季铵化。杂原子O,N和S可以位于杂烷基的任何内部位置。杂原子Si可以位于杂烷基的任何位置,包括烷基连接到分子其余部分的位置。实施例包括-CH2-CH2-O-CH3,-CH2-CH2-NH-CH3,-CH2-CH2-N(CH3)-CH3,-CH2-S-CH2-CH3,-CH2-CH2,-S(O)-CH3,-CH2-CH2-S(O)2-CH3,-CH=CH-O-CH3,-Si(CH3)3,-CH2-CH=N-OCH3,和-CH=CH-N(CH3)-CH3。最多两个杂原子可以是连续的,例如-CH2-NH-OCH3和-CH2-O-Si(CH3)3。类似地,除非另有说明,术语“杂烯基”和“杂炔基”其本身或与另一个术语的组合分别指烯基或炔基,其分别含有指定数目的碳和1至3个选自O,N,Si和S的杂原子,且其中氮和硫原子可选地被氧化,氮杂原子可任选地被季铵化。杂原子O,N和S可以位于杂烷基的任何内部位置。
术语“杂亚烷基”本身或作为另一取代基的一部分是指由杂烷基衍生的饱和或不饱和或多不饱和的二价基团,例如-CH2-CH2-S-CH2CH2-和-CH2-S-CH2-CH2-NH-CH2-,-O-CH2-CH=CH-,-CH2-CH=C(H)CH2-O-CH2-和-S-CH2-C≡C-。对于杂亚烷基,杂原子也可以占据链末端中的任一个或两个(例如,亚烷基氧基,亚烷基二氧基,亚烷基氨基,亚烷基二氨基等)。
术语"烷氧基"、"烷氨基"和"烷硫基"(或硫代烷氧基)以其常规意义使用,指代分别经氧原子、氨基或硫原子连接于分子的其余部分的那些烷基。此外,对于二烷基氨基,烷基部分可以相同或不同,也可和与各烷基相连的氮原子组合形成3-7元环。因此,-NRaRb所示基团表示包括哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基(azetidinyl)等。
除非另有表述,术语“卤代”或“卤素”本身或作为另一取代基的一部分是指氟、氯、溴、或碘原子。此外,诸如“卤代烷基”等术语表示包括单卤代烷基或多卤代烷基。例如,术语“C1-4卤代烷基”表示包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
除非另有表述,术语“芳基”表示多不饱和的(通常芳香性)的烃基,其可以是单环或稠合在一起或共价连接的多环(最多三环)。术语"杂芳基"是指含有1至5个选自N、O、和S的杂原子的芳基(或环),其中氮和硫原子任选被氧化,氮原子任选被季铵化。杂芳基可通过杂原子连接于分子的其余部分。芳基的非限制性例子包括苯基、萘基和联苯基,而杂芳基的非限制性例子包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、苯并三嗪基(benzotriazinyl)、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异噁唑基、异苯并呋喃基(isobenzofuryl)、异吲哚基、中氮茚基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等等。以上芳基和杂芳基环系统各自的取代基选自下述可接受的取代基的组。
为简洁起见,当术语“芳基”与其它术语(例如芳氧基,芳硫基,芳烷基)组合使用时,包括如上所定义的芳基和杂芳基环。因此,术语“芳烷基”是指包括其中芳基连接到与分子的其余部分连接的烷基的那些基团(例如苄基,苯乙基,吡啶基甲基等)。
在一些实施例中,上述术语(如“烷基”,“芳基”和“杂芳基”)将包括指定基团的取代和未取代形式。下面提供了每种类型基团的优选取代基。为简洁起见,术语芳基和杂芳基将指代如下文所提供的取代或未取代的形式,而术语“烷基”和相关的脂肪族基团是指未取代的形式,除非指明被取代。
烷基(包括通常称为亚烷基,烯基,炔基和环烷基的那些基团)的取代基可以是选自下组的各种基团:-卤素、-OR'、-NR'R”、-SR'、-SiR'R”R”'、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R”、-OC(O)NR'R”、-NR”C(O)R'、-NR'-C(O)NR”R”'、-NR”C(O)2R'、-NH-C(NH2)=NH、-NR'C(NH2)=NH、-NH-C(NH2)=NR'、-S(O)R'、-S(O)2R'、-S(O)2NR'R”、-NR'S(O)2R”、-CN和-NO2,数量从零到(2m'+1),其中m'是这种基团中的碳原子总数。R'、R”和R”'各自独立地表示氢,未取代的C1-8烷基,未取代的杂烷基,未取代的芳基,被1-3个卤素取代的芳基,未取代的C1-8烷基,C1-8烷氧基或C1-8硫代烷氧基,或未取代的芳基-C1-4烷基。当R'和R”连接到相同的氮原子时,它们可以与氮原子结合形成3-,4-,5-,6-或7-元环。例如,-NR'R”是指包括1-吡咯烷基和4-吗啉基。术语“酰基”,单独或作为另一基团的一部分使用,是指其中在最接近该基团的连接点的碳上两个取代基的被取代基=O取代(例如-C(O)CH3,-C(O)CH2CH2OR'等)。
类似地,芳基和杂芳基的取代基是多种的,并且通常选自:-卤素、-OR'、-OC(O)R'、-NR'R”、-SR'、-R'、-CN、-NO2、-CO2R'、-CONR'R”、-C(O)R'、-OC(O)NR'R”、-NR”C(O)R'、-NR”C(O)2R'、-NR'-C(O)NR”R”'、-NH-C(NH2)=NH、-NR'C(NH2)=NH、-NH-C(NH2)=NR'、-S(O)R'、-S(O)2R'、-S(O)2NR'R”、-NR'S(O)2R”、-N3、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,数量从零到芳香环体系上的开放化合价的总数;其中R'、R”和R”'独立地选自氢,C1-8烷基,C3-6环烷基,C2-8烯基,C2-8炔基,未取代的芳基和杂芳基,(未取代的芳基)-C1-4烷基和未取代的芳氧基-C1-4烷基。其它合适的取代基包括通过1-4个碳原子的亚烷基链连接到环原子上的每一个上述芳基取代基。
芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-T-C(O)-(CH2)q-U-的取代基取代,其中T和U独立地为-NH-,-O-,-CH2-或单键,且q是0至2的整数。或者,芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-A-(CH2)r-B-,其中A和B独立地是-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-、-S(O)2NR'-或单键,且r是1至3的整数。由此形成的新环中的一个单键可以任选地被双键取代。或者,芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-(CH2)s-X-(CH2)t-的取代基替代,其中s和t独立地为0至3的整数,并且X是-O-、-NR'-、-S-、-S(O)-、-S(O)2-、或-S(O)2NR'-。-NR'-和-S(O)2NR'-中的取代基R'选自氢或未取代的C1-6烷基。
如本文所用,术语“杂原子”意在包括氧(O)、氮(N)、硫(S)和硅(Si)。
对于本文提供的化合物,从取代基(通常为R基团)到芳香环(例如苯,吡啶等)的中心的键将被理解为是指在芳香环的任何可用顶点提供连接的键。在一些实施例中,该描述也包括稠合在芳环上的环上的连接。例如,绘制到吲哚苯部分的中心的键将表示与吲哚的六元或五元环部分的任何可用顶点连接的键。
术语"药学上可接受的盐"意在包括活性化合物与相对无毒的酸或碱制备的盐,其取决于本文所述化合物上具体的取代基。当本发明化合物含有相对酸性的官能团时,可通过将中性形式的此类化合物与充足量的所需碱(无溶剂的或在合适的惰性溶剂中的)接触来获得碱加成盐。衍生自药学上可接受的无机碱的盐的例子包括铝、铵、钙、铜、铁,亚铁、锂、镁、锰,亚锰、钾、钠、锌等。衍生自药学上可接受的有机碱的盐包括伯胺、仲胺和叔胺的盐,包括取代的胺、环状胺、自然产生的胺等等,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺(glucamine)、葡萄糖胺(glucosamine)、组氨酸、海巴明、异丙胺、赖氨酸、甲葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等等。当本发明化合物含有相对碱性的官能团时,可通过将中性形式的此类化合物与充足量的所需酸(无溶剂的或在合适的惰性溶剂中的)接触来获得酸加成盐。药学上可接受的酸加成盐的例子包括衍生自无机酸的那些,例如盐酸、氢溴酸、硝酸、碳酸、单氢碳酸、磷酸、单氢磷酸、二氢磷酸、硫酸、单氢硫酸、氢碘酸、或亚磷酸等等;以及衍生自相对无毒的有机酸的盐,例如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、扁桃酸、苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸,酒石酸、甲磺酸等等。还包括氨基酸的盐,例如精氨酸盐等等,和有机酸的盐,例如葡萄糖醛酸(glucuronic acid)或半乳糖醛酸(galactunoric acid)等(参见,例如Berge,S.M.等,“药学上的盐(PharmaceuticalSalts)”,Journal of Pharmaceutical Science,1977,66,1-19)。本发明的某些具体化合物同时含有碱性和酸性官能团,从而能将化合物转换成碱加成盐或酸加成盐。
通过将盐与碱或酸接触并以常规方式分离母体化合物,可以再生该化合物的中性形式。化合物的母体形式与各种盐形式在某些物理性能(例如在极性溶剂中的溶解度)上不同,但除此之外,就本发明的目的而言,那些盐与母体形式化合物是等价的。
除盐形式外,本发明提供前药形式的化合物。本文所述的化合物的前药是在生理条件下很容易经历化学变化以提供本发明化合物的那些化合物。另外,前药可以在离体环境中通过化学或生物化学方法转变为本发明化合物。例如,当置于含合适的酶或化学试剂的经皮贴片贮器中时,前药可缓慢转变为本发明的化合物。
本发明的某些化合物可以非溶剂化形式以及溶剂化形式存在,包括水化形式。溶剂化形式通常与非溶剂化形式等价,应包括在本发明范围内。本发明的某些化合物可以多晶型或无定形形式存在。通常,就本发明所考虑的应用而言,所有物理形式是等价的,应包括在本发明范围内。
本发明的某些化合物拥有不对称碳原子(光学中心)或双键;消旋体、非对映体、几何异构体、区域异构体和单独的异构体(例如,分离的对映体)均应包括在本发明范围内。当本文提供的化合物具有确定的立体化学(表示为R或S,或具有虚线或楔形键指明)时,被本领域技术人员将理解那些化合物为基本上不含其他异构体(例如至少80%,90%,95%,98%,99%和至多100%不含其他异构体)。
本发明化合物还可在构成此类化合物的一个或多个同位素原子处含有非天然比例的原子同位素。某同位素的非天然比例可以定义为从所讨论原子的天然发现的量到100%该原子的量。例如,化合物可以掺入放射性同位素,例如氚(3H)、碘-125(125I)或碳-14(14C),或非放射性同位素,例如氘(2H)或碳-13(13C)。除了本申请所述的那些用途,此类同位素变体可提供额外的用途。例如,本发明化合物的同位素变体可以有额外的用途,包括但不限于作为诊断的和/或成像试剂,或作为细胞毒性/放射毒性治疗剂。另外,本发明化合物的同位素变体可具有改变的药代动力学和药效学特征,从而有助于增加治疗期间的安全性、耐受性或疗效。无论是否有放射性,本发明化合物的所有同位素变体均应包括在本发明范围内。
靶向蛋白酶降解平台TED
本发明提供基于本发明偶联物的靶向蛋白酶降解平台(TED),该平台利用了细胞内的“清洁工”-泛素-蛋白酶体系统。
典型地,基于本发明TED技术,可利用细胞自身的蛋白质破坏机制来从细胞中去除特定致癌病蛋白,因此是一种靶向治疗的替代方法。
与传统蛋白抑制剂作用原理不同,本发明的TED技术是一个双功能杂合化合物,一边用来结合目标蛋白,另一边用来结合一个E3连接酶,使得目标蛋白可以与E3连接酶结合,把目标蛋白泛素化,从而被蛋白组降解。理论上TED技术只是提供结合活性,不需直接抑制目标蛋白的功能活性,又可以重复利用,因此,具有优异的应用前景。
靶向配体
靶向配体(或靶蛋白部分或靶蛋白配体或配体)是能够结合目标靶蛋白的小分子。
本申请的一些实施方案涉及靶标分子,代表性的靶标分子其包括但不限于:叶酸、Hsp90抑制剂、激酶抑制剂、MDM2抑制剂、靶向含人BET溴结构域的蛋白的化合物、靶向胞质信号蛋白FKBP12的化合物、HDAC抑制剂、人赖氨酸甲基转移酶抑制剂、血管生成抑制剂、免疫抑制化合物和靶向芳基烃受体(AHR)的化合物。
在某些实施方案中,靶向配体是能够结合激酶、BET含溴结构域的蛋白、胞质信号蛋白(例如FKBP12)、核蛋白、组蛋白脱乙酰酶、赖氨酸甲基转移酶、调节血管生成的蛋白、调节免疫应答的蛋白、芳烃受体(AHR)、雌激素受体、雄激素受体、糖皮质激素受体或转录因子(例如,SMARCA4、SMARCA2、TRIM24)。
在某些实施方案中,靶向配体能够结合的激酶包括但不限于:酪氨酸激酶(例如AATK、ABL、ABL2、ALK、AXL、BLK、BMX、BTK、CSF1R、CSK、DDR1、DDR2、EGFR、EPHA1、EPHA2、EPHA3、EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHA10、EPHB1、EPHB2、EPHB3、EPHB4、EPHB6、ERBB2、ERBB3、ERBB4、FER、FES、FGFR1、FGFR2、FGFR3、FGFR4、FGR、FLT1、FLT3、FLT4、FRK、FYN、GSG2、HCK、IGF1R、ILK、INSR、INSRR、IRAK4、ITK、JAK1、JAK2、JAK3、KDR、KIT、KSR1、LCK、LMTK2、LMTK3、LTK、LYN、MATK、MERTK、MET、MLTK、MST1R、MUSK、NPR1、NTRK1、NTRK2、NTRK3、PDGFRA、PDGFRB、PLK4、PTK2、PTK2B、PTK6、PTK7、RET、ROR1、ROR2、ROS1、RYK、SGK493、SRC、SRMS、STYK1、SYK、TEC、TEK、TEX14、TIE1、TNK1、TNK2、TNNI3K、TXK、TYK2、TYRO3、YES1或ZAP70)、丝氨酸/苏氨酸激酶(例如酪蛋白激酶2、蛋白激酶A、蛋白激酶B、蛋白激酶C、Raf激酶、CaM激酶、AKT1、AKT2、AKT3、ALK1、ALK2、ALK3、ALK4、AuroraA、AuroraB、AuroraC、CHK1、CHK2、CLK1、CLK2、CLK3、DAPK1、DAPK2、DAPK3、DMPK、ERK1、ERK2、ERK5、GCK、GSK3、HIPK、KHS1、LKB1、LOK、MAPKAPK2、MAPKAPK、MNK1、MSSK1、MST1、MST2、MST4、NDR、NEK2、NEK3、NEK6、NEK7、NEK9、NEK11、PAK1、PAK2、PAK3、PAK4、PAK5、PAK6、PIM1、PIM2、PLK1、RIP2、RIP5、RSK1、RSK2、SGK2、SGK3、SIK1、STK33、TAO1、TAO2、TGF-β、TLK2、TSSK1、TSSK2、ΜLK1或ΜLK2)、周期素依赖性蛋白激酶(例如Cdk1-Cdk11)和富含亮氨酸的重复激酶(例如LRRK2)。
靶标分子
在本发明的式I所示的偶联物中,通过靶标分子来结合靶标蛋白。
在本发明中,靶标分子可以是靶标分子A、靶标分子T、或其组合。
在本发明中,所述靶标分子可以是所述靶标蛋白的任意一种抑制剂。所述靶标分子可以是所述靶标蛋白的高效抑制剂,也可以活性比较差的抑制剂。具体地,本发明的靶标分子可以是针对本领域任一种靶标蛋白的本领域已知的小分子抑制剂。
在某些实施方案中,本文所用的靶标分子具有可与连接头进行连接的基团(如-O-,-NRa-(其中,Ra为H、或C1-C6烷基等取代基,-CO-、-COO-等等),以一价与本发明的连接体分子(如本发明中L1)对接成醚、胺、酰胺等等。
所述靶标蛋白可以是本领域已知的各种靶标蛋白,代表性的例子包括(但并不限于):MDM2、AKT、BCR-ABL、Tau、BET(BRD2,BRD3,BRD4)、ERRα、FKBP12、RIPK2、ERBB3、雄激素受体、MetAP2、TACC3、FRS2α、PI3K、DHFR、GST、Halo Tag、CRABPI,CRABPII、RAR、芳烃受体、雌激素受体。不同的靶标蛋白和一些相应的抑制剂可市售获得或用常规方法制备。例如,对于MDM2,其抑制剂可参见WO 2017176957、WO2017176958A1等文献。
E3连接酶配体
在本发明中,E3连接酶配体用来结合E3连接酶。代表性的E3连接酶配体具有如下所示的结构:
上式中,RX为O、NH、S、CO或SOn(n为1或2)等;RY为CH2、C=S、CO;而且,所述E3连接酶配体(式I中的B)可通过其中的RX基团与本发明的L1进行连接,如-Rx-L1-A(如-O-L1-A)。
上式中,R’为H或Me,R为H、Me或Et。
在某些实施方案中,本文所用E3连接酶配体具有可与连接头进行连接的基团(如-O-,-NRa-(其中,Ra为H、或C1-C6烷基等取代基),-CO-、-COO-等等),以一价与本发明的连接体分子(如如本发明中L1等)对接成醚、胺、酰胺等等。
连接体分子(如本文中所述的L1)
本发明的连接体分子用于连接靶标分子和E3连接酶配体。例如通过两端的官能团(例如-OH、-SH、-NH2、-NHR、-SOOH或-COOH)与靶标分子或E3连接酶配体连接;其中,取代或未取代的C1-C10烷基、-(C=O)-R’、(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’或-NH-CO-NH-R’、-NH-CO-O-R’或-X’-L3-Z;;其中L3为连接基团,而Z为多肽元件(如配体、抗体或其肽段等)或者靶向分子如具有靶向功能的小分子(如叶酸、HSP90抑制剂等)。
优选地,当所述连接头为-(CH2)s-;其中,1-4个-CH2-被含有1-4个杂原子(如N、O、S和P)的五元不饱和环替换时,所述连接体分子如下所示:
式中,X、Y、T、V、Q、W、m、n、s、R的定义如上。
优选地,当所述连接头为-(CH2)s-;其中,1-4个-CH2-被O或含有1个氮原子的4-6元饱和环替换时,本发明的连接体分子具体可以选自如下结构:
式中,X、Y、p、m、n、s、R的定义如上。
优选地,本发明的连接体分子选自如下结构:
式中,X和Y的定义如上,m为1-20的整数;p为1-3的整数。
优选地,当所述连接头为-(CH2)s-或所述连接头为-(CH2)s-;其中,1-4个-CH2-被O替换。优选地,本发明的连接体分子还能过通过-X’-L3-连接体结构再与靶标分子或者多肽元件连接形成三功能的靶向蛋白酶降解平台(TED)分子,例如,如下式所示的靶向蛋白酶降解平台(TED)分子:
靶向蛋白酶降解平台(TED)分子
本发明的靶向蛋白酶降解平台(TED)分子结构如式Ia或式I所示:
靶标分子-连接体-E3连接酶配体 式Ia。
A-L1-B 式I
式中,A、L1和B的定义如本发明第一方面中所述。
连接体和偶联方法
本发明的连接体L1用于连接靶标分子和E3连接酶配体。
优选地,所述靶标分子或E3连接酶配体可以通过-O-、-S-、-NH-、-NR-、-(C=O)-、-(C=O)O-、-SO2-等基团连接。
在本发明的连接体上,还可进一步含有其它各种官能团,例如-OH、-NHR、-SH等官能团。
典型地,本发明的连接体L1,可以以下通式II表示:
-X-L2-Y- 式II
式中,X、L2、Y的定义如本发明第一方面中所述。
在另一优选例中,X和Y各自独立地以下一价基团失去1个氢原子形成的二价所形成的二价基团:-OH、-NH2、-SH、-COOH、-SO2H。
具体地,连接体与靶标分子的连接方式可以通过如下所示的连接基团进行连接:
其中,上述各式中的R如上定义;n为1或2或3。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1
制备表A中所示的L1-B偶联物,其中,在偶联物结构式中用H替换结构E3连接酶配体B后,即为相应的连接体L1分子。
表A
实施例2偶联物的制备
(2.1)TED分子的制备操作1:
称取化合物UBI-1005(20mg,0.042mmol)溶解在DMF(2mL)中,冰水浴下依次加入NH2-Linker-B1(1eq.),HATU(2eq.32mg,0.084mmol)和DIEA(3eq.16.2mg,0.126mmol)。加料完成后,物料体系在氮气保护下室温搅拌反应18小时,反应完成后将反应液倒入5mL水中,用乙酸乙酯提取三次(5mL*3).合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品后以展开剂极性(DCM/MeOH=10/1)进行薄层色谱硅胶板分离制备得到相应的TED化合物。
通过类似方式,制得表B1中所示的A-L1-B偶联物。
表B1
(2.2)TED分子的制备操作2:
称取化合物UBI-1005(20mg,0.042mmol)溶解在DMF(2mL)中,冰水浴下依次加入NH2-Linker(L1)-B2(1eq.),HATU(2eq.32mg,0.084mmol)and DIEA(3eq.16.2mg,0.126mmol)。加料完成后,物料体系在氮气保护下室温搅拌反应18小时,反应完成后将反应液倒入5mL水中,用乙酸乙酯提取三次(5mL*3).合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品后以展开剂极性(DCM/MeOH=10/1)进行薄层色谱硅胶板分离制备得到相应的TED化合物。
通过类似方式,制得表B2中所示的A-L1-B偶联物。
表B2
(2.3)TED分子的制备操作3:
称取化合物UBI-1001(20mg,0.043mmol)溶解在DMF(2mL)中,冰水浴下依次加入NH2-Linker(L1)-B1(1eq.),HOBT(2eq.23mg,0.086mmol),EDCI(2eq.16.4mg,0.086mmol)and TEA(3eq.13mg,0.129mmol)。加料完成后,物料体系在氮气保护下室温搅拌反应18小时,反应完成后将反应液倒入5mL水中,用乙酸乙酯提取三次(5mL*3).合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品后以展开剂极性(DCM/MeOH=10/1)进行薄层色谱硅胶板分离制备得到目标化合物TED。
通过类似方式,制得表B3中所示的A-L1-B偶联物。
表B3
(2.4)TED分子的制备操作4:
称取化合物UBI-1001(20mg,0.043mmol)溶解在DMF(2mL)中,冰水浴下依次加入NH2-Linker-B2(1eq.),HOBT(2eq.23mg,0.086mmol),EDCI(2eq.16.4mg,0.086mmol)andTEA(3eq.13mg,0.129mmol)。加料完成后,物料体系在氮气保护下室温搅拌反应18小时,反应完成后将反应液倒入5mL水中,用乙酸乙酯提取三次(5mL*3).合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品后以展开剂极性(DCM/MeOH=10/1)进行薄层色谱硅胶板分离制备得到目标化合物TED。
通过类似方式,制得表B4中所示的A-L1-B偶联物。
表B4
(2.5)TED分子的制备操作5:
称取化合物UBI-1007(20mg,0.0436mmol)溶解在无水DMF(1mL)中,冰水浴下依次加入NH2-Linker-B1(0.0436mmol),HATU(33mg,0.0872mmol)和DIEA(0.072mL,0.436mmol),加料完成后,物料体系在氮气保护下室温搅拌反应18小时,反应完成后将反应液倒入5mL水中,用乙酸乙酯提取三次(5mL*3).合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品后以展开剂极性(DCM/MeOH=10/1)进行薄层色谱硅胶板分离制备得目标化合物。
通过类似方式,制得表B5中所示的A-L1-B偶联物。
表B5
(2.6)TED分子的制备操作6:
称取化合物UBI-1007(20mg,0.0436mmol)溶解在无水DMF(1mL)中,冰水浴下依次加入NH2-Linker-B2(0.0436mmol),HATU(33mg,0.0872mmol)和DIEA(0.072mL,0.436mmol),加料完成后,物料体系在氮气保护下室温搅拌反应18小时,反应完成后将反应液倒入5mL水中,用乙酸乙酯提取三次(5mL*3).合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品后以展开剂极性(DCM/MeOH=10/1)进行薄层色谱硅胶板分离制备得目标化合物。
通过类似方式,制得表B6中所示的A-L1-B偶联物。
表B6
(2.7)TED分子的制备实实例操作7:
称取化合物UBI-1008(20mg,0.0436mmol)溶解在无水DMF(1mL)中,冰水浴下依次加入NH2-Linker-B1(0.0436mmol),HATU(33mg,0.0872mmol)和DIEA(0.072mL,0.436mmol),加料完成后,物料体系在氮气保护下室温搅拌反应18小时,反应完成后将反应液倒入5mL水中,用乙酸乙酯提取三次(5mL*3).合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品后以展开剂极性(DCM/MeOH=10/1)进行薄层色谱硅胶板分离制备得目标化合物。
通过类似方式,制得表B7中所示的A-L1-B偶联物。
表B7
(2.8)TED分子的制备操作8:
称取化合物UBI-1008(20mg,0.0436mmol)溶解在无水DMF(1mL)中,冰水浴下依次加入NH2-Linker-B2(0.0436mmol),HATU(33mg,0.0872mmol)和DIEA(0.072mL,0.436mmol),加料完成后,物料体系在氮气保护下室温搅拌反应18小时,反应完成后将反应液倒入5mL水中,用乙酸乙酯提取三次(5mL*3).合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品后以展开剂极性(DCM/MeOH=10/1)进行薄层色谱硅胶板分离制备得目标化合物。
通过类似方式,制得表B8中所示的A-L1-B偶联物。
表B8
测试例1生物学测试
1.1本发明化合物对MV4;11细胞增殖抑制作用的生物学测定
实验材料:
实验方法:
1)缓冲液配制
MV4;11细胞培养液:Iscove's Modified DμLbecco's Medium加10%FBS和1/100pen-strep。
2)实验步骤:
(1)MV4;11细胞用细胞培养液传代培养,取生长状态良好的细胞接种于96孔板,每孔100μL,每孔细胞数为20000,于37℃,5%CO2细胞孵育箱中培养过夜。
(2)将药物用二甲基亚砜(DMSO)配置成10mM的储存液。将化合物稀释(以此保证培养体系中DMSO浓度为1%),每个浓度做2个孔重复。取稀释好的化合物加到细胞培养孔(终浓度为100μM,33μM,11μM…),轻轻振荡混匀。另外设置2个只加细胞的阴性对照孔(保证培养体系中DMSO浓度为1%)。
3)结果检测:
(1)培养72小时后,每孔加50μL Cell Titer-Glo,室温孵育10分钟。
(2)用Envision读取化学发光信号值。
(3)数据用软件GraphPad Prism中Dose-response-inhibition方程分析,得出IC50值。
1.2本发明化合物PLK1蛋白表达生物学测定
实验材料:
实验方法:
1)缓冲液配制
2)实验步骤:
(1)MV4;11细胞用细胞培养液传代培养后,取生长状态良好的细胞接种于6孔板,每孔2ml,每孔细胞数为100万,于37℃,5%CO2细胞孵育箱中培养过夜。
(2)将药物用二甲基亚砜(DMSO)配置成10mM的储存液。取稀释好的化合物加到细胞培养孔(保证培养体系中DMSO浓度为0.1%),轻轻振荡混匀。另外设置阴性对照孔(加等量DMSO)。
(3)培养6小时后,用RIPA细胞裂解液裂解细胞,提取蛋白,用BCA试剂盒测蛋白浓度。加2X蛋白上样缓冲液,100℃加热10分钟后样品放-20℃保存。
(4)每孔蛋白量为25μg的蛋白量上样到聚丙烯酰胺凝胶,进行电泳。
(5)蛋白质从聚丙烯酰胺凝胶转移到PVDF膜上,加5%脱脂牛奶室温封闭1小时。
(7)二抗(Anti-rabbit IgG,HRP-linked Antibody)室温孵育1小时,再用TBST溶液洗膜三次每次10分钟。
3)结果检测:
最后加显色液(SuperSignalTMWest Femto Maximum Sensitivity Substrate)显色,用自动化学发光仪(ChemiDoc XRS+(BIO-RAD))拍照,收集图片,分析。
1.3本发明化合物对PLK1酶活性抑制作用的生物学测定
实验材料:
实验方法:
1)缓冲液配制
酶反应缓冲液:使用ddH2O稀释5X缓冲液至1X,加入50uM DTT。
2)实验步骤:
(1)使用1X缓冲液稀释酶,底物和ATP。
(2)加入2μL2.5X酶溶液至每个孔。
(3)加入1μL稀释好的化合物至每个孔,室温孵育15分钟。
(4)加入2μL2.5X底物/ATP混合液到每个孔,室温孵育1个小时。
(5)加入5μLADP-glo至每个孔,室温孵育40分钟。
(6)加入10μL检测试剂,室温孵育30分钟。
3)结果检测:
(1)使用Envision读取化学发光信号值。
(2)数据用软件GraphPad Prism中Dose-response-inhibition方程分析,得出IC50值。
1.4本发明化合物BRD4(Bromodomain containing protein 4)蛋白表达生物学测定
测试方法类似1.2PLK1蛋白表达生物学测定。
1.5本发明化合物PLK1(Polo‐like kinase 1)蛋白表达生物学测定
测试方法类似1.2PLK1蛋白表达生物学测定。
1.6生物测试结果
1.2、1.4及1.5的蛋白表达测试结果如图2所示。
以下分子对MV4;11细胞抑制活性IC50在0.1nM-10M之间:UB-180510,UB-180519,UB-180523,UB-180525,UB-180529,UB-180537,UB-180539,UB-180541,UB-180545,UB-180552,UB-180553,UB-180554,UB-180564,UB-180566,UB-180594,UB-180601,UB-180602。
以下分子对Hela细胞抑制活性IC50在0.1nM-10M之间:UB-180512,UB-180525。
以上结果表明,本发明提供了一类靶向蛋白酶降解(TED)分子,由靶向作用于目标蛋白的小分子化合物单元、E3泛素连接酶结合单元和连接单元组成,能够与PLK和/或BRD4蛋白进行结合,促使PLK1和/或BRD4蛋白更易被蛋白酶降解,从而起到抑制细胞增殖的作用,可以作为蛋白降解的药物。本发明提供的化合物对MV4-11细胞增殖具有很好的抑制作用,说明本发明化合物可以制备成为抗肿瘤药物,特别是用于治疗急性髓细胞性白血病(Acute myeloid leukemia,AML)。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种式I所示的偶联物:
A-L1-B 式I
其中:
所述A为靶标分子的一价基团;
所述B为E3连接酶配体的一价基团;
所述L1为连接A和B的连接头;且L1如下式II所示:
-X-L2-Y- 式II
其中,
当X或Y为NH或NR时,X或Y与和它们相连的L2链中的一部分共同形成4-8元芳香或非芳香杂环;其中,R为取代或未取代的C1-C10烷基、-(C=O)-R’、(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’或-NH-CO-NH-R’、-NH-CO-O-R’或-X’-L3-Z;其中L3为连接基团,而Z为多肽元件或者靶标分子T;其中,R’选自下组的基团:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、氨基保护基、或者-X’-L3-Z;
或
X和Y各自独立地选自下组:-O-、-S-、-NH-、-NR-、-(C=O)NH-、-NH(C=O)-、-SO2-、-NHSO2-、-SO2NH-、-SO-、-NHSO-、-SONH-、-PO3-、-NHCOO-、-COO-、-NHCOCH2O-、或-NH-CO-NH-;其中,R为取代或未取代的C1-C10烷基、-(C=O)-R’、-(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’或-NH-CO-NH-R’、或-X’-L3-Z;;
其中,L3为连接基团,而Z为多肽元件或者靶标分子T;其中,R’选自下组的基团:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、保护基、或者-X’-L3-Z;
X’选自下组:-O-、-S-、-NH-、-(C=O)NH-、-NH(C=O)-、-SO2-、-NHSO2-、-SO2NH-、-SO-、-NHSO-、-SONH-、-PO3-、-NHCOO-、-COO-、-COOCH2-或-NH-CO-NH-;
L2和L3各自独立地为选自下组的连接基团:
(a)取代或未取代的5-20元碳链;
(b)取代或未取代的含有1-5个选自N、O和S的杂原子的5-20元杂碳链;
(c)取代或未取代的5-20元碳链,且链中的1-4个链原子被选自下组的杂环替换:含有1-4个选自N、O和S的杂原子的4-10元饱和杂环、含有1-4个选自N、O和S的杂原子的5-10元部分不饱和或完全不饱和杂环;
(d)取代或未取代的含有1-5个选自N、O和S的杂原子的5-20元杂碳链,且链中的1-4个链原子被选自下组的杂环替换:含有1-4个选自N、O和S的杂原子的4-10元饱和杂环、含有1-4个选自N、O和S的杂原子的5-10元部分不饱和或完全不饱和杂环;
其中,所述“取代”指基团上的一个或多个(优选为1、2、3、或4个)氢原子被选自下组的取代基所取代:C1-C10烷基、C3-C8环烷基、-COOH、-OH、-SH、-NH2、-NHR、-N(R1)R2、-Z、-X’-L3-Z、 其中,Z为多肽元件或者靶标分子T;其中,当取代基为-Z时,则-Z仅仅位于N原子上;其中,R1和R2各自独立地为H、C1-C6烷基、C3-C8环烷基、氨基保护基、-X’-L3-Z其中,R为取代或未取代的C1-C10烷基、-(C=O)-R’、(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’或-NH-CO-NH-R’、-NH-CO-O-R’或-X’-L3-Z;;其中L3为连接基团,而Z为多肽元件或者靶标分子T;其中,R’选自下组的基团:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、保护基、或者X’-L3-Z。
2.如权利要求1所述的偶联物,其特征在于,L2和/或L3为选自下组的连接基团:
(a)取代或未取代的-(CH2)s-;
(b)取代或未取代的-(CH2)s-,其中,1-5个-CH2-被O替换;
(c)取代或未取代的-(CH2)s-,其中,1-2个-CH2-被NR替换和任选地1-2个-CH2-被O替换;其中,R为H、氨基保护基或X’-L3-Z;
(d)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被含有1-4个选自N、O、S和P的杂原子的五元不饱和杂环替换;
(e)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被含有1-4个选自N、O、S和P的杂原子的4-6元饱和杂环替换;
(f)取代或未取代的-(CH2)s-,其中,1-4个-CH2-被O和含有1-4个选自N、O、S和P的杂原子的4-6元饱和杂环替换;
(g)二价的含有1-2个氮原子的4-6元杂环基团;
其中,s为5-20的整数。
4.如权利要求1所述的偶联物,其特征在于,L1选自下组:
式中,“Y,X”表示该末端为X或Y;附加条件是一端为X,而另一端为Y;
X和Y如上定义,m和n各自独立地为0-15的整数;
T、V、Q、和W各自独立地为CH、C=O、S、O、NH或NR;R为C1-C10烷基、-(C=O)-R’、-(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’、-NH-CO-NH-R’、-NH-CO-O-R’或N-X’-L3-Z;其中L3为连接基团,而Z为多肽元件或者靶标分子T;R’、X’如上定义。
6.一种药物组合物,其特征在于,所述的药物组合物含有如权利要求1-7任一项所述的偶联物和药学上可接受的载体。
8.如权利要求1-7任一项所述的偶联物的用途,其特征在于,用于制备用于治疗与靶标蛋白过量相关的疾病的药物组合物。
9.一种减少细胞中靶标蛋白含量的方法,其特征在于,将细胞与权利要求1-7任一项所述的偶联物相接触,从而减少细胞中靶标蛋白的含量。
10.一种减少对象中靶标蛋白含量或治疗与与靶标蛋白过量相关的疾病,其特征在于,包括步骤:给需要的对象施用权利要求1-7任一项所述的偶联物。
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CA3115871A1 (en) | 2020-04-16 |
EP3865152A4 (en) | 2022-11-16 |
CN112955182A (zh) | 2021-06-11 |
EP3865152A1 (en) | 2021-08-18 |
AU2019357908A1 (en) | 2021-06-03 |
WO2020073930A1 (zh) | 2020-04-16 |
JP2022513360A (ja) | 2022-02-07 |
US20210369853A1 (en) | 2021-12-02 |
CN111018857B (zh) | 2023-06-02 |
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