CN115210381A - 新型降解相关相互作用的检测 - Google Patents
新型降解相关相互作用的检测 Download PDFInfo
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Abstract
本发明涉及使用诱饵和猎物系统检测和鉴定蛋白质‑蛋白质或蛋白质‑小分子相互作用的方法。它还涉及用于本文所述方法的诱饵和猎物蛋白、小分子和构建体。
Description
发明领域
本发明特别涉及蛋白质-蛋白质或蛋白质-小分子相互作用和/或新型小分子的检测和鉴定。
相关申请的交叉引用
本申请要求2019年12月17日提交的美国临时申请第62/949,026的权益,将其全部内容并入本文。
以电子方式提交的文本文件的说明
同此以电子方式提交的文本文件的内容通过引用完整并入本文:序列表的计算机可读格式拷贝(文件名:ORN-064PC_ST25.txt;创建日期:2020年12月7日;文件大小:10,365字节)。
背景技术
分子相互作用,比如蛋白质/蛋白质和蛋白质/小分子相互作用,是许多(如果不是全部)生物过程的关键部分。分子相互作用的增强或阻断可用作治疗策略;然而,临床相关分子相互作用的鉴定通常是有问题的。
对蛋白质-蛋白质相互作用(PPI)的角色的日益了解引导了稳定化/诱导蛋白质之间的相互作用而不是破坏它们或阻断它们的酶活性的药剂的探索。分子胶是指小分子PPI稳定剂,其结合蛋白质并调节其分子表面,从而使其能够募集新的蛋白质,或稳定化弱的蛋白质-蛋白质相互作用。这些化合物,最值得注意的是免疫调节药物来那度胺,它与E3连接酶蛋白小脑蛋白(cerebIon)(CRBN)相互作用并驱动下游蛋白质降解,在治疗各种癌症方面表现出优异的疗效。某些分子胶还可以通过与在蛋白质-蛋白质相互作用界面处产生的结构特异性结合来稳定化弱的蛋白质-蛋白质相互作用而起作用。在这种情况下,分子胶将仅结合其中两种蛋白质相互作用的构型,而本文概述的情况是,其中分子胶(比如来那度胺)首先与一种蛋白质结合,然后诱导或增强该复合物与另一种蛋白质接合。
因而,仍然需要用于检测分子相互作用的新的更稳健的方法。
发明内容
本发明部分地涉及用于检测各种分子相互作用的基于细胞的系统。在一些实施方案中,本发明提供了允许询问/鉴定使用标准测定法不可检测的分子相互作用(例如,蛋白质/蛋白质、蛋白质/小分子和/或受小分子调节的蛋白质/蛋白质相互作用)的方法。在一些实施方案中,本文公开的方法允许鉴定可用于开发针对疾病的疗法的蛋白质之间的临床相关或显著的分子相互作用。
在一些实施方案中,本文公开的方法包括诱饵蛋白和多种猎物蛋白。这样的方法可用于鉴定在诱饵蛋白与多种猎物蛋白或单个猎物蛋白之间的分子相互作用。在一些实施方案中,本发明使用哺乳动物蛋白质-蛋白质相互作用陷阱测定法(MAPPIT,参见Eyckerman等人“Design and application of a cytokine-receptor-based interaction trap,”Nat Cell Biol.2001Dec;3(12):1114-9和Lievens,等人“Proteome-scale BinaryInteractomics in Human Cells,”Molecular&Cellular Proteomics 15.12(2016):3624-3639,通过引用将其完整并入本文)。然而,本文所述的MAPPIT衍生的测定法通过使用与诱饵或猎物蛋白相互作用的小分子以及在一些实施方案中的其他特征而得到增强。在一些实施方案中,通过小分子(在本文中也描述为“化合物”或“配体”或“药物”)促进/诱导在诱饵蛋白和猎物蛋白之间的分子相互作用。在实施方案中,所述小分子为不是杂合配体的化学实体。在实施方案中,所述小分子是单一化学实体。在实施方案中,所述小分子不具有接头。在实施方案中,所述小分子仅与诱饵或猎物蛋白之一直接相互作用。在实施方案中,小分子是作为杂合配体的化学实体,具有以下一者或多者:CRBN结合分子、PEG接头和小分子。
在各种实施方案中,本发明涉及通过以下方式检测分子相互作用的方法:(a)提供具有基于配体的嵌合受体的细胞,所述嵌合受体包含(i)来源于第一受体的配体结合结构域的细胞外部分和(ii)第一受体或第二受体的跨膜和细胞质结构域并且具有与其融合的胞内E3连接酶底物结合亚基诱饵蛋白,其中所述第二受体的跨膜和/或细胞质结构域包含减少或消除STAT(信号转导和转录激活因子)募集的突变;(b)表达与细胞中的受体片段融合的猎物蛋白,所述受体片段包含功能性STAT募集位点;和(c)检测指示分子相互作用的信号。在实施方案中,小分子与E3连接酶底物结合亚基的结合促进了与猎物蛋白的结合和蛋白质复合物的形成,所述蛋白复合物包含支架蛋白、与小分子复合的E3连接酶底物结合亚基和猎物蛋白。
在一些实施方案中,所述猎物蛋白与受体片段融合。在一些实施方案中,所述猎物蛋白与受体片段的N端或C端融合。在实施方案中,所述猎物蛋白与gp130或其片段融合。在实施方案中,所述猎物蛋白与gp130或其片段的N端或C端融合。
在实施方案中,所述第一受体和第二受体是相同的。
在实施方案中,E3连接酶底物是内源的或由转基因表达。
在各种实施方案中,本发明涉及通过以下方式检测分子相互作用的方法:(a)提供具有基于配体的嵌合受体的细胞,所述嵌合受体包含(i)来源于第一受体的配体结合结构域的细胞外部分和(ii)第一受体或第二受体的跨膜和细胞质结构域并且具有与其融合的支架蛋白,其中所述第二受体的跨膜和/或细胞质结构域包含减少或消除STAT(信号转导和转录激活因子)募集的突变;(b)表达与细胞中的受体片段融合的猎物蛋白,所述受体片段包含功能性STAT募集位点;和(c)检测指示分子相互作用的信号。在实施方案中,支架蛋白与E3连接酶底物结合亚基相互作用,并且支架蛋白和E3连接酶底物结合亚基的复合物与猎物相互作用。
在一些实施方案中,在猎物蛋白和诱饵蛋白之间的相互作用引起与诱饵蛋白融合的受体片段募集到跨膜嵌合受体蛋白,从而恢复STAT分子的配体依赖性跨膜嵌合受体信号传导和激活。在一些实施方案中,所述细胞包含STAT反应性报告基因。在一些实施方案中,激活的STAT分子迁移至细胞核并诱导STAT反应性报告基因的转录,并且在一些情况下,报告基因信号允许检测和/或发现分子相互作用。
在一些实施方案中,检测到的相互作用是将诱饵和/或猎物募集到二元、三元或更高阶蛋白质复合物中。
在一些实施方案中,分子相互作用是蛋白质/蛋白质相互作用。在一些实施方案中,分子相互作用是由小分子介导的蛋白质/蛋白质相互作用(例如,所述方法进一步包括引入与猎物蛋白或诱饵蛋白结合的小分子)。具体地说,在一些实施方案中,分子相互作用是通过小分子与猎物蛋白质或诱饵蛋白结合介导的蛋白质/蛋白质相互作用。例如,本发明方法可以检测复合物形成。在一些实施方案中,小分子诱导猎物蛋白或诱饵蛋白的疏水表面或结合位点的暴露,从而允许与猎物蛋白或诱饵蛋白相互作用。在一些实施方案中,小分子是分子胶或二价杂合配体分子(例如但不限于PROTAC)。
举例来说,在一些实施方案中,检测到的相互作用涉及例如但不限于与免疫调节药物(IMiD)接触的E3连接酶蛋白,所述免疫调节药物例如,沙利度胺、来那度胺和泊马度胺,以及与其相关的化合物或与等效或相似的结构口袋和小分子结合位点结合的化合物,所述结构口袋和小分子结合位点通常被IMiD化合物和与其相关的化合物占据。
在一些实施方案中,本发明方法适用于VHL作为E3连接酶底物结合诱饵蛋白的用途。与CRBN相似,VHL是E3连接酶的底物结合亚基。因此,与作为诱饵的E3连接酶有关的所有实施方案同样适用于VHL作为诱饵。
在实施方案中,本发明方法适用于使用FKBP12蛋白或这个家族的成员而不是E3连接酶作为诱饵(因此,与E3连接酶作为诱饵有关的所有实施方案同样适用于FKBP蛋白或这个家族的成员例如但不限于FKBP12作为诱饵)。
在一些实施方案中,本发明方法允许展示其中它不被表达为受体融合蛋白的诱饵蛋白。在这种情况下,可以与诱饵蛋白相互作用的不同蛋白质,即支架蛋白,与受体蛋白融合。诱饵与这种蛋白质的相互作用产生了蛋白质复合物,所述复合物有效地将诱饵蛋白展示为所述复合物的一部分。这提供了展示诱饵蛋白的新方法,所述诱饵蛋白呈不需要其与受体融合的形式。举例来说,并且在本文中证明,E3连接酶蛋白复合物的另一组分与受体融合,所述受体例如DDB1(或与E3连接酶的底物识别组分天然地相互作用的任何其他支架蛋白)。至于DDB1,这种作为受体融合物表达的蛋白质随后与单独表达(例如,作为非融合蛋白)的CRBN诱饵蛋白相互作用,从而在模拟它通过E3连接酶向底物呈递的自然形式的环境中展示它。同时暴露于分子胶和多种猎物蛋白使得能够发现响应于CRBN与诸如IMiD的分子胶结合而与DDB1-CRBN复合物相互作用的猎物蛋白。类似地,通过类推,在一些实施方案中,包含除CRBN之外的配体结合诱饵蛋白(比如VHL或任何其他E3连接酶组分)并且不是表达的受体融合蛋白的多蛋白复合物可以这种方式展示为诱饵。
在一些实施方案中,本发明方法适用于筛选与诱饵和/或化合物相互作用的多种猎物蛋白。
在各种实施方案中,本发明方法涉及基于阵列的形式,例如其中编码各种猎物蛋白的cDNA被点样在表面上。在各种实施方案中,本发明方法涉及基于细胞群的方法,其中例如将猎物蛋白库引入细胞中,使得平均而言,每个细胞表达单一猎物。在这样的实施方案中,在与化合物和/或诱饵相互作用后,鉴定了编码cDNA以揭示所述相互作用。在实施方案中,采用FACS或微流体分离进行所述鉴定。
在一些实施方案中,本发明方法适用于筛选与猎物蛋白和/或诱饵蛋白相互作用的多种化合物(例如化合物库)。在其中所述化合物不含接头(例如,不含杂合配体)的实施方案中,本发明方法允许进行筛选,而没有由于接头附着所致的对化合物相互作用部分的可能干扰。
在一些实施方案中,本发明方法适用于VHL作为E3连接酶底物结合诱饵蛋白的用途。与CRBN相似,VHL是E3连接酶的底物结合亚基(因此,所有与E3连接酶作为诱饵相关的实施方案同样适用于VHL作为诱饵)。
在一些实施方案中,本发明方法适用于使用FKBP或这个家族的成员而不是E3连接酶作为非受体融合物的诱饵(因此,所有与E3连接酶作为非受体融合物的诱饵相关的实施方案同样适用于FKBP或这个家族的成员,例如FKBP12作为诱饵)。
附图说明
图1A-B显示了描述本发明MAPPIT衍生概念的非限制性示意图。在图1A中,E3连接酶底物结合亚基诱饵蛋白(“B”)与嵌合受体的C端融合。这种嵌合受体,例如,具有I型细胞因子受体(“CYT”)的细胞外部分和受体的跨膜和细胞内结构域,其经由诱变而在STAT募集方面有缺陷。这种嵌合受体有信号传导缺陷。当与融合到含有功能性STAT募集位点的受体片段的猎物蛋白(“P”)共表达时,受体复合物在功能上得到补充,并且在某些情况下,在细胞因子配体刺激(L)后,STAT信号传导被恢复。STAT分子被激活并迁移到细胞核,并且诱导STAT反应性报告基因的转录。在图1B中显示了类似于图1A的示意图,但描述了本发明的MAPPIT衍生概念,其涉及以非受体融合的形式展示诱饵蛋白。交叉影线部分是支架蛋白。
图2A-L在MAPPIT衍生测定法中募集选定的底物的CRBN结合化合物的评估。在MAPPIT衍生测定法中评估了由一组CRBN底物的指示的CRBN IMiD配体(沙利度胺,THL;来那度胺,LEN;泊马度胺,POM;CC-122;CC-220;CC-885)诱导的募集。MAPPIT是先前描述的双杂交技术系统的变型(Lemmens,等人“MAPPIT,a mammalian two-hybrid method for in-cell detection of protein-protein interactions”,Methods Mol Biol.2015;1278:447-55,将其全部内容通过引用并入本文)并被更详细地概述于实施例1中。该测定法需要将CRBN诱饵受体融合物与gp130融合的底物融合物一起共转染。评估了测试化合物随着测试化合物浓度增加的活性(剂量反应研究),以监测促进CRBN-配体诱导的蛋白质相互作用的能力-即,募集任何指示的新底物:IKZF1、GSPT1、GSPT2和未公开的底物。如所示,获得的结果再现了用此处描述的不同技术生成的文献已知数据。例如,任何指示的化合物都导致IKZF1募集,而GSPT1和GSPT2仅通过CC-885募集。
图3A-D多个CRBN MAPPIT衍生物受体构建体能够检测化合物依赖性底物相互作用。如在实施例2中更详细讨论的,多种受体融合物构型可应用于此处使用的MAPPIT-衍生测定法中。典型的融合蛋白由与突变的瘦素受体的跨膜和细胞内部分融合的EPO受体的细胞外结构域组成(图3A-B)。然而,细胞外EPO受体结构域可以与瘦素受体的结构域交换,从而产生由瘦素而不是EPO激活的测定系统(图3C-D)。类似地,可以使用替代的gp130融合蛋白,其中部分gp130结构域可以融合到感兴趣的蛋白质的N端或C端。在这里,我们应用多种CRBN诱饵受体融合构建体类型和底物gp130融合物测试了CC-220和CC-885依赖性CRBN与IKZF1和GSPT1底物的相互作用。用基于EPO受体的CRBN受体融合物(pSEL-CRBN)和基于瘦素受体的变体(pCLG-CRBN)获得了相似结果。同样,不同的gp130融合物版本(N端或C端融合物)产生可比较的数据。另外,我们表明,多种版本的底物蛋白,例如IKZF1同工型1与7或GSPT1同工型1(全尺寸)与仅覆盖结构域2和3的部分构建体产生了相似结果。在每组直方图中,最左边的条为0μM,右边的下一个条为0.1μM,右边的下一个条为1μM,并且最右边的条为10μM。
图4可以使用应用DDB1受体融合物约替代性MAPPIT衍生测定配置来检测CRBN化合物依赖性底物相互作用。测试了替代性CRBN底物结合测定法,其中DDB1融合到MAPPIT嵌合受体构建体(pSEL-DDB1),并且未融合的CRBN诱饵蛋白与底物gp130融合蛋白IKZF1(gP130-IKZF1)或未公开的底物蛋白(gp130-targetX)一起共表达。在不存在CRBN共表达的情况下(“无CRBN”),不会观察到来那度胺(LEN)诱导的信号。然而,当共转染未融合的CRBN表达构建体时,获得了针对IKZF1和靶标X两者的相互作用的LEN依赖性信号。在每组直方图中,最左边的条为0μM LEN,右边的下一个条为0.1μM LEN,右边的下一个条为1μM LEN,并且最右边的条为10μM LEN。
图5未融合的DDB1的共表达提高了MAPPIT衍生的化合物依赖性CRBN底物相互作用测定法的灵敏度。在用于分子胶诱导的CRBN-IKZF1相互作用的MAPPIT衍生测定设置中,评价了共转染未融合的DDB1表达构建体的效果。测定配置与图2A-L中应用的配置相似,其中CRBN诱饵受体构建体(pSEL-CRBN)和IKZF1(同工型7)gp130融合构建体在没有或有另外的DDB1表达载体的情况下共表达。在不存在或存在DDB1共表达的情况下,对于每种测试的分子胶(与图2A-L中使用的组相同),观察到报告信号的化合物浓度依赖性诱导。有趣的是,与其中DDB1过表达的设置中的最大信号相比,在测试的较低浓度处观察到信号增加,表明所述测定法的灵敏度高于在不存在DDB1共表达的情况下的灵敏度。在每组直方图中,最左边的条为0μM,右边的下一个条为0.1μM,右边的下一个条为1μM,并且最右边的条为10μM。
图6DDB1-CRBN MAPPIT-衍生物受体融合物使得能够检测化合物依赖性底物募集。在这里测试了一种测定配置,其中DDB1-CRBN基因融合物被栓系到MAPPIT嵌合受体构建体(pSEL-DDB1-CRBN)上,并且在存在浓度增加的一组分子胶(与图2A-L中使用的组相同)的情况下针对gp130-IKZF1(同工型7)底物融合物进行测试。同样,这种测定配置能够以化合物剂量依赖性方式再现化合物诱导的CRBN-IKZF1复合物形成。在每组直方图中,最左边的条为0μM,右边的下一个条为0.1μM,右边的下一个条为1μM,并且最右边的条为10μM。
图7A-B BRD4底物向CRBN的ARV-825PROTAC依赖性募集可以在MAPPIT中检测到。图3A-D中测试的替代性MAPPIT衍生的CRBN诱饵受体融合物,其含有EPO受体细胞外结构域(pSEL-CRBN)或瘦素受体细胞外结构域(pCLG-CRBN),与BRD4(同工型3)的N端或C端gp130融合物融合。在这两种测定法中,ARV-825PROTAC(CRBN结合配体和BRD4结合化合物的化学融合物)诱导了剂量依赖性萤光素酶报告信号。在每组直方图中,从左到右,条形代表如下:0μM ARV-825;0.0003μM ARV-825;0.003μM ARV-825;0.03μM ARV-825;0.3μM ARV-825;3μMARV-825;和30μM ARV-825。
图8A-F MAPPIT-衍生测定法使得能够检测在FKBP1A(FKBP12)和MTOR或钙调神经磷酸酶之间的化合物依赖性相互作用。使用与MTOR(FRB结构域)或钙调神经磷酸酶PPP3CA催化亚基gp130融合蛋白组合的FKBP1A诱饵受体融合物(pSEL-FKBP1A)评价与已知靶蛋白的化合物依赖性FKBP1A相互作用。如所示,用雷帕霉素和依维莫司两者都检测到化合物诱导的MTOR募集。类似地,也可以监测PPP3CA的FK506或吡美莫司依赖性结合。值得注意的是,在钙调神经磷酸酶结合的情况下,PPP3R2调节亚基的共表达显著增大了信号窗口。
图9A-B可以在MAPPIT中检测到杂合配体诱导的BRD4底物向VHL的募集。在这里,VHL诱饵蛋白融合到含有EPO受体细胞外结构域(pSEL-VHL)或瘦素受体细胞外结构域(pCLG-VHL)的MAPPIT衍生的嵌合受体构建体上。这些构建体与图7中使用的BRD4(同工型3)的相同N末端或C末端gp130融合物或未融合的gp130阴性对照构建体结合。用一定浓度范围的MZ1(VHL和BRD4配体的化学融合物)处理表达VHL和BRD4构建体的细胞,从而诱导剂量依赖性MAPPIT信号。当测试未融合的gp130对照构建体时,未获得信号。在每组直方图中,最左边的条为0μM MZ1,右边的下一个条为0.1μM MZ1,右边的下一个条为1μM MZ1,并且最右边的条为10μM MZ1。
图10A-C化合物集合的筛选鉴定了能够将IKZF1募集到CRBN的新型分子胶。使用在图2A-L中应用的MAPPIT衍生测定法筛选96个IMiD和IMiD样化合物的集合,其中CRBN诱饵受体构建体(pSEL-CRBN)和IKZF1(同工型7)gp130融合构建体共表达。在初步筛选中,以3个剂量(低、中和高浓度)测试化合物并确定萤光素酶报告信号。在图10A-C中显示的曲线代表化合物处理的样品和DMSO处理的对照(左图)两者的萤光素酶信号频率分布。化合物处理样品的曲线是双峰的,其中右移峰覆盖展示出其报告信号高于DMSO处理对照的报告信号的化合物。对于展示出反应并因此代表诱导IKZF1募集到CRBN的化合物的三种化合物,显示了剂量反应命中确认(右图)。初步筛选中每个测试浓度的相应信号由线标记指示,其中线类型对应于剂量反应曲线中使用的类型(点线、虚线或实线)。这些样品曲线表明,这种方法能够鉴定跨越宽的效能范围的分子胶。
图11A-B ORF cDNA文库筛选检测了新型分子胶诱导的CRBN新底物。在这里,以基于细胞微阵列的筛选格式应用MAPPIT衍生测定法,用于筛选人ORF(eome)cDNA文库,以便响应于CC-220(一种已知的IMiD药物和CRBN配体)将靶标募集到CRBN。测定了在以阵列格式显示的细胞簇内的细胞中的蛋白质和小分子相互作用。细胞微阵列中的每个点对应于这样的细胞簇,所述细胞簇表达单个ORF/蛋白质候选物,所述候选物正在经受配体诱导的(在这种情况下是CC-220诱导的)与CRBN的相互作用的测试。正相互作用被读出为细胞荧光的增加。显示的是来自细胞微阵列筛选的荧光强度数据的点图,所述筛选跨越/针对大量单个ORF/靶蛋白候选物。X轴显示粒子计数,并且Y轴显示微阵列中每个细胞簇的积分强度。如所显示和指示的,观察到许多ORF cDNA的显著信号诱导。对于显示出反应并因此代表通过CC-220分子胶(由箭头指示)募集到CRBN的蛋白质的四个ORF cDNA,生成剂量反应曲线,以证实其与CRBN的CC-220剂量依赖性结合。这些实例表明,这种MAPPIT衍生筛选方法使得能够鉴定新型分子胶诱导的CRBN底物。
图12A-B杂合配体化合物筛选鉴定了感兴趣的靶蛋白的已知配体和新型配体。使用MAPPIT衍生测定法筛选与感兴趣的靶白结合的甲氧苄啶(TMP)融合的杂合配体分子的集合。在此测定法中,利用TMP对DHFR的高亲和力将TMP杂合配体锚定到DHFR受体融合物上,并将所述TMP连接的化合物作为诱饵展示。在图12A中,使用MAPPIT衍生测定法,其中DHFR受体融合物(在这种情况下是一种受体融合蛋白,其含有瘦素受体的细胞外结构域;pCLG-DHFR)与雌激素受体(ESR1)的gp130融合物共表达,用于筛选320个成员的杂合配体多样性集(含有来自多样性集合的化合物,每个化合物通过PEG接头与TMP连接),其中掺入了他莫昔芬(TAM)的TMP融合物,他莫昔芬为已知的ESR1配体。以单剂量筛选化合物,并确定萤光素酶报告信号。在图12A中显示的曲线代表化合物处理的样品和DMSO处理的对照(左图)两者的萤光素酶信号频率分布。正如对多样性集预期的那样,除了化合物处理的信号高于DMSO对照信号的少数化合物以外,两者的分布在很大程度上重叠。这些命中之一对应于TMP-TAM(频率曲线上的实线标记)。如文献中报道,剂量反应分析证实了获得的TMP-TAM与ESR1结合的信号,其中EC50在低纳摩尔范围内。应用相似的筛选设置来鉴定MDM4的新型配体,其为经验证的癌症靶蛋白。在图12B中提供的杂合配体筛选中鉴定了单个命中,其可以在剂量反应后续实验中得到证实。这些实例表明,在这里应用的MAPPIT衍生测定法可用于鉴定感兴趣的特定靶蛋白的新型配体。
图13A-B通过基于阵列的ORF cDNA文库筛选鉴定新型杂合配体靶标。在这里,使用如在图12A-B中描述的MAPPIT衍生测定法,应用如在图11A-B中使用的基于细胞微阵列的筛选方法来筛选人ORF(eome)eDNA文库的TMP融合的杂合配体的靶标。将感兴趣的化合物,在这种情况下是具有靶标未知的强的抗肿瘤表型的未公开化合物,显示为锚定在DHFR受体融合物上的TMP杂合配体诱饵,并且检测与由排列的ORF cDNA gp130融合物编码的任何蛋白质的相互作用,表示为阵列上相应点的细胞荧光增加。显示的点图代表来自细胞微阵列筛选的荧光数据,所述筛选跨越/针对大量单个ORF/靶蛋白候选物。X轴显示粒子计数,并且Y轴显示微阵列中每个细胞簇的积分强度。如所示,观察到特定ORF cDNA的强信号(由箭头指示),并且这种相互作用可以在剂量反应分析中得到证实。此数据展示,在这里描述的MAPPIT衍生筛选方法使得能够通过使用TMP衍生的配体融合分子来鉴定配体的新型靶标。
图14在FKBP蛋白和MTOR之间的雷帕霉素诱导的结合的鉴定。在MAPPIT衍生测定法中评价了FKBP蛋白家族的不同成员(FKBP1A/FKBP12、FKBP3、FKBP4和FKBP5)的MTOR(FRB结构域)募集,其中FKBP蛋白被表达为含有Epo受体细胞外结构域的MAPPIT受体融合物(pSEL-FKBPx),并且MTOR(FRB)融合到gp130上。如所示,对于每个测试的FKBP蛋白,获得了雷帕霉素剂量依赖性信号,与已发表的报告一致。在每组直方图中,最左边的条为0nM雷帕霉素,右边的下一个条为1nM雷帕霉素,右边的下一个条为10nM雷帕霉素,并且最右边的条为100nM帕霉素。
具体实施方式
本公开部分地基于发现基于细胞的系统和方法,所述系统和方法允许询问使用标准测定法不可检测的分子相互作用(例如,蛋白质/蛋白质、蛋白质/小分子和/或受小分子调节的蛋白质/蛋白质相互作用)。
在一个方面,本发明方法考虑到用于检测分子相互作用的方法,所述方法包括:(a)提供包含基于配体的嵌合受体的细胞,所述嵌合受体包含(i)来源于第一受体的配体结合结构域的细胞外部分和(ii)这样的第一受体或第二受体的跨膜和细胞质结构域,并且具有与其融合的细胞内E3连接酶底物结合亚基诱饵蛋白,其中所述受体构建体的跨膜和/或细胞质结构域包含减少或消除STAT募集的突变;(b)表达与细胞中的受体片段融合的猎物蛋白,所述受体片段包含功能性STAT募集位点;和(c)检测指示分子相互作用的信号。
在各种实施方案中,本发明涉及通过以下方式检测分子相互作用的方法:(a)提供具有基于配体的嵌合受体的细胞,所述嵌合受体包含(i)来源于第一受体的配体结合结构域的细胞外部分和(ii)第一受体或第二受体的跨膜和细胞质结构域并且具有与其融合的支架蛋白,其中所述受体构建体的跨膜和/或细胞质结构域包含减少或消除STAT(信号转导和转录激活因子)募集的突变;(b)表达与细胞中的受体片段融合的猎物蛋白,所述受体片段包含功能性STAT募集位点;和(c)检测指示分子相互作用的信号。在实施方案中,支架蛋白与E3连接酶底物结合亚基相互作用,并且支架蛋白和E3连接酶底物结合亚基的复合物与猎物相互作用。
在一些方面,本发明方法考虑到用于检测分子相互作用的方法,所述方法包括:(a)提供包含基于配体的嵌合受体的细胞,所述嵌合受体包含(i)来源于第一受体的配体结合结构域的细胞外部分和(ii)这样的第一受体或第二受体的跨膜和细胞质结构域,并且具有与其融合且可以与细胞内E3连接酶底物结合亚基诱饵蛋白相互作用的一种蛋白质(或更多种),其中所述受体构建体的跨膜和/或细胞质结构域包含减少或消除STAT募集的突变;(b)表达与细胞中的受体片段融合的猎物蛋白,所述受体片段包含功能性STAT募集位点;和(c)检测指示分子相互作用的信号。在实施方案中,诱饵蛋白与支架蛋白和E3连接酶底物结合亚基诱饵结合。在实施方案中,诱饵蛋白与跨膜蛋白直接融合。
在一些实施方案中,诸如本文所述的系统中的猎物蛋白和诱饵蛋白之间的相互作用引起蛋白质复合物的形成,所述蛋白复合物包含与猎物蛋白融合的受体片段。将这样的受体片段募集到复合物中,从而将其定位为受体相关JAK激酶(例如,JAK2)的可用底物,恢复配体依赖性受体信号传导和STAT分子的激活。在一些实施方案中,所述细胞包含STAT反应性报告基因。在一些实施方案中,激活的STAT分子迁移至细胞核并诱导STAT反应性报告基因的转录,并且在一些情况下,报告基因信号允许检测和/或发现分子相互作用。
在一些实施方案中,分子相互作用是蛋白质/蛋白质相互作用。在一些实施方案中,诱饵和猎物两者都是蛋白质。
本发明还包括分析化合物库。在实施方案中,诱饵与化合物结合,并且任选地该诱饵-化合物复合物与猎物相互作用。因此,在实施方案中,本发明方法允许检测和/或发现新型化合物介导的蛋白质/蛋白质相互作用和/或新型蛋白质/化合物相互作用。在实施方案中,本发明方法允许检测和/或发现充当分子胶的新型化合物。在实施方案中,本发明方法允许检测和/或发现将弱的诱饵-猎物相互作用转化为更强的诱饵-猎物相互作用的新型化合物。
在一些实施方案中,诱饵是或包含调节泛素-蛋白酶体系统的蛋白质。在一些实施方案中,诱饵是或包含E3连接酶蛋白或调节E3连接酶蛋白的蛋白质。在一些实施方案中,诱饵是或包含滞蛋白-环(cullin-RING)连接酶(CRL)蛋白或调节CRL蛋白的蛋白质。在各种实施方案中,诱饵是或包含CRL4蛋白或调节CRL4蛋白的蛋白质。在一些实施方案中,诱饵是或包含DDB1-CUL4相关因子(DCAF)蛋白或调节DCAF的蛋白质。
在一些实施方案中,诱饵是或包含小脑蛋白(cereblon)(CRBN)和冯·希佩尔-林道(Von Hippel Lindau,VHL)中的一种或多种。
在实施方案中,CRBN或VHL与本文所述的跨膜结构域融合。在实施方案中,CRBN或VHL未与如本文所述的跨膜结构域融合,例如,它在与融合至如本文所述的跨膜结构域的支架蛋白相互作用时作为诱饵起作用。
在实施方案中,诱饵是E3连接酶底物结合亚基。
在实施方案中,E3连接酶底物结合亚基选自任何以下基因编码的蛋白质:AMFR、ANAPC11、APG16L、ARIH1、ARIH2、ARPC1A、ARPC1B、ASB2、ASB2、ATG16L1、BAF250、BARD1、BIRC2、BIRC3、BIRC4、BIRC7、BMI1、BRAP、BRCA1、bTrCP、CBL、CBLB、CBLC、CBLL1、CCIN、CCIN、CCNB1IP1、CRBN、CHFR、CHIP、CNOT4、COP1、CSA、DCAF1、DCAF10、DCAF11、DCAF12、DCAF13、DCAF14、DCAF15、DCAF16、DCAF17、DCAF19、DCAF2、DCAF3、DCAF4、DCAF5、DCAF6、DCAF7、DCAF8、DCAF9、Dda1、DDB2、DET1、DNAI2、DTX3、DZIP3、E6AP、EDD、EED、ENC1、ENC1、FANCL、FBXL1、FBXL10、FBXL11、FBXL12、FBXL13、FBXL14、FBXL15、FBXL16、FBXL17、FBXL18、FBXL19、FBXL20、FBXL21、FBXL22、FBXL3、FBXL4、FBXL5、FBXL7、FBXL8、FBXO1、FBXO10、FBXO11、FBXO12、FBXO13、FBXO14、FBXO15、FBXO16、FBXO17、FBXO18、FBXO19、FBXO2、FBXO20、FBXO21、FBXO22、FBXO3、FBXO4、FBXO5、FBXO6、FBXO7、FBXO8、FBXW1、FBXW10、FBXW11、FBXW12、FBXW5、FBXW7、FBXW8、FBXW9、FEM1A、FEM1B、FEM1C、GAN、GAN、GNB1、GNB2、GNB5、GRWD1、GTF2H2、GTF3C2、HACE1、HECTD1、HECTD2、HECTD3、HERC1、HERC2、HERC3、HERC4、HERC5、HERC6、HLTF、HOIP、HUWE1、IBRDC2、IBRDC3、IFRG15、IPP、IPP、ITCH、IVNS1ABP、IVNS1ABP、KATNB1、KBTBD10、KBTBD10、KBTBD11、KBTBD11、KBTBD12、KBTBD12、KBTBD13、KBTBD13、KBTBD2、KBTBD2、KBTBD3、KBTBD3、KBTBD4、KBTBD4、KBTBD5、KBTBD5、KBTBD6、KBTBD6、KBTBD7、KBTBD7、KBTBD8、KBTBD8、KCTD5、KEAP、KEAP1、KIAA0317、KIAA0614、KLHDC5、KLHL1、KLHL1、KLHL10、KLHL10、KLHL11、KLHL11、KLHL12、KLHL12、KLHL13、KLHL13、KLHL14、KLHL14、KLHL15、KLHL15、KLHL17、KLHL17、KLHL18、KLHL18、KLHL2、KLHL2、KLHL20、KLHL21、KLHL21、KLHL22、KLHL22、KLHL23、KLHL23、KLHL24、KLHL24、KLHL25、KLHL25、KLHL26、KLHL26、KLHL28、KLHL28、KLHL29、KLHL29、KLHL3、KLHL3、KLHL30、KLHL30、KLHL31、KLHL31、KLHL32、KLHL32、KLHL33、KLHL33、KLHL34、KLHL34、KLHL35、KLHL35、KLHL36、KLHL36、KLHL38、KLHL38、KLHL4、KLHL4、KLHL5、KLHL5、KLHL6、KLHL6、KLHL7、KLHL7、KLHL8、KLHL8、KLHL9、KLHL9、LINCR、LNX1、LRR1、LRRC41、LRSAM1、LZTR1、LZTR1、MAGEA1、MAGE-A1、MAGEA2、MAGE-A2、MAGEA3、MAGE-A3、MAGEA6、MAGE-A6、MAGEB18、MAGE-B18、MAGEB2、MAGE-B2、MAGEC2、MAGE-C2、MALIN、MAP3K1、MARCH1、MARCH11、MARCH2、MARCH4、MARCH5、MARCH6、MARCH7、MARCH8、MARCH9、MDM2、MDM4、MEX、MGRN1、MIB1、MIB2、MID1、MKRN1、MNAT1、MUF1、MULAN、MURF、MYCBP2、MYLIP、Nedd4、NEDD4L、NEDL1、NEDL2、NEURL、NEURL2、NLE1、NUP43、OSTM1、PAFAH1B1、PARC、PARK2、PCGF1、PCGF2、PDZRN3、PEX10、PEX7、PJA1、PJA2、POC1A、PPIL2、PRAME、PRPF19、PWP1、RACK1、RAD18、RAE1、RAG1、RBBP4、RBBP5、RBBP6、RBBP7、RBCK1、RBX1、RCHY1、RFFL、RFPL4A、RFWD2、RING1、RNF103、RNF11、RNF111、RNF114、RNF12、RNF123、RNF125、RNF128、RNF13、RNF130、RNF133、RNF135、RNF138、RNF139、RNF14、RNF144A、RNF167、RNF168、RNF180、RNF181、RNF182、RNF185、RNF19、RNF2、RNF20、RNF20、RNF216、RNF25、RNF34、RNF4、RNF40、RNF41、RNF43、RNF43、RNF5、RNF6、RNF7、RNF8、RNF85、RPTOR、SCAP、SH3RF1、SHPRH、SIAH1、SIAH2、SMU1、SMURF1、SMURF2、SOCS1、SOCS3、SPOP、SPSB1、SPSB1、SPSB2、SPSB2、SPSB4、SPSB4、STXBP5L、SYVN1、TAF5L、TBL1Y、THOC3、TLE1、TLE2、TLE3、TOPORS、TRAF2、TRAF6、TRAF7、TRAIP、TRIAD3、TRIM1、TRIM10、TRIM11、TRIM12、TRIM13、TRIM14、TRIM15、TRIM16、TRIM17、TRIM18、TRIM2、TRIM21、TRIM22、TRIM23、TRIM24、TRIM25、TRIM26、TRIM27、TRIM28、TRIM29、TRIM29、TRIM3、TRIM31、TRIM32、TRIM33、TRIM36、TRIM37、TRIM39、TRIM40、TRIM41、TRIM44、TRIM45、TRIM47、TRIM5、TRIM50、TRIM52、TRIM54、TRIM55、TRIM58、TRIM59、TRIM62、TRIM65、TRIM66、TRIM7、TRIM71、TRIM8、TRIM9、TRIP12、TRPC4AP、TSSC1、UBE3B、UBE3C、UBE4A、UBE4B、UBOX5、UBR1、UBR2、UBR3、UBR4、UHRF1、UHRF2、VHL、VPS18、WDR12、WDR23、WDR26、WDR3、WDR31、WDR37、WDR39、WDR4、WDR47、WDR48、WDR5、WDR51B、WDR53、WDR57、WDR59、WDR5B、WDR61、WDR76、WDR77、WDR82、WDR83、WDR86、WSB1、WSB2、WWP1、WWP2、ZNF294、ZNF313、ZNF364、ZNRF1、ZNRF2、ZYG11A、ZYG11B或ZYG11BL。
在实施方案中,E3连接酶底物结合亚基是CRBN或VHL。
在实施方案中,支架蛋白与E3连接酶底物结合亚基相互作用,并且支架蛋白和E3连接酶底物结合亚基的复合物与猎物相互作用。
在实施方案中,支架选自BIRC6、CUL3、DDB1、ELOB、ELOC、RBX1、SKP1、UBCH5A、UBE2A、UBE2B、UBE2B2、UBE2C、UBE2D1、UBE2D2、UBE2D3、UBE2D4、UBE2E1、UBE2E2、UBE2E3、UBE2F、UBE2G1、UBE2G2、UBE2H、UBE2J1、UBE2J2、UBE2K、UBE2L3、UBE2L6、UBE2M、UBE2N、UBE2NL、UBE2O、UBE2Q1、UBE2Q2、UBE2QL、UBE2R1、UBE2R2、UBE2S、UBE2T、UBE2U、UBE2V1、UBE2V1、UBE2V2和UBE2W。
在一些实施方案中,支架蛋白选自受损的DNA结合蛋白1(DDB1)、滞蛋白-4A(CUL4A)和滞蛋白1调节剂(ROC1)。
在各种实施方案中,诱饵包括小脑蛋白(CRBN)、受损的DNA结合蛋白1(DDB1)、滞蛋白-4A(CUL4A)、滞蛋白1的调节剂(ROC1)和冯·希佩尔-林道(VHL)中的一种或多种。
在一些实施方案中,猎物是CRBN的底物和/或新底物。在实施方案中,CRBN的底物和/或新底物包含具有i-残基的b-发夹a-转角,所述i-残基带有具有氢键受体的侧链,比如Asx或ST基序,其中氢键在i的侧链和i+3的主链NH之间以及在i的主链羰基氧和i+4的主链NH之间。在实施方案中,所述i+4残基是甘氨酸(非限制性实例包括GSPT1、CK1a)。在实施方案中,CRBN的底物和/或新底物具有b-发夹a-转角,其中残基i和i+3是半胱氨酸,并且i+4残基是甘氨酸。两个Cys残基与锌离子结合以加强转角的形状(非限制性示例包括IKZF1、ZnF692和在“Defining the human C2H2 zinc finger degrome targeted bythalidomide analogs through CRBN”,Sievers等人,Science,第362卷,第6414期,DOI:10.1126/science.aat0572(2018),通过引用完整并入本文中报道的所有底物)。在实施方案中,CRBN的底物和/或新底物具有“伪环”,即在i+3位带有甘氨酸的b-发夹b-转角。可以通过i-1侧链的氢键受体和i+3甘氨酸的羰基之间的氢键来加强转角结构。
在实施方案中,CRBN是指包含任何CRBN的氨基酸序列的多肽,比如人CRBN蛋白(例如,人CRBN同工型1(GenBank登录号NP_057386);或人CRBN同工型2(GenBank登录号NP_001166953),将其各自通过引用完整并入本文),以及相关的多肽,包括其SNP变体。相关的CRBN多肽包括等位基因变体(例如SNP变体);剪接变体;片段;衍生物;取代、缺失和插入变体;融合多肽;和种间同源物,在某些实施方案中,其保留CRBN活性并且/或者足以产生抗CRBN免疫应答。
在一些实施方案中,猎物是Ikaros(IKZF1)、Helios(IKZF2)、Aiolos(IKZF3)、Eos(IKZF4)、Pegasus(IKZF5)、SALL4、CSNK1A、CK1a和ZFP91中的一种或多种。在各种实施方案中,猎物是Ikaros(IKZF1)、Helios(IKZF2)、Aiolos(IKZF3)、Eos(IKZF4)、Pegasus(IKZF5)、SALL4、CSNK1A、CK1a和ZFP91中的一种或多种。在一些实施方案中,猎物是Ikaros(IKZF1)、Helios(IKZF2)、Aiolos(IKZF3)、Eos(IKZF4)、Pegasus(IKZF5)、SALL4、CSNK1A、CK1a和ZFP91中的一种或多种。
在一些实施方案中,本发明方法涉及一种或多种E3连接酶底物结合亚基,例如但不限于作为诱饵的CRBN和VHL(或与支架蛋白比如DDB1、CUL4A和ROC1结合的诱饵,与CRBN或VHL接触),并且所述诱饵与本文所述的化合物(例如,与一个或多个E3连接酶底物结合亚基例如但不限于CRBN和VHL结合的化合物,例如,IMiD)接触以发现与所述诱饵相互作用的蛋白质猎物,因为它受到所述化合物的调节。例如,所述方法鉴定了接触诱饵的相互作用猎物,其中所述诱饵被所述化合物修饰。在一些实施方案中,由于与诱饵的相互作用,猎物被募集和/或降解。在这样的实施方案中,不是为了限制,所述猎物不直接与所述化合物相互作用。
在一些实施方案中,本发明方法允许鉴定CRBN的新的底物或新底物。
在一些实施方案中,本发明方法涉及一种或多种E3连接酶底物结合亚单位,例如但不限于作为诱饵的CRBN和VHL(或与支架蛋白比如DDB1、CUL4A和ROC1结合的诱饵,与CRBN或VHL接触),并且在与诱饵(例如但不限于E3连接酶底物结合亚基的底物或新底物)相互作用的蛋白质猎物存在的情况下,将诱饵与测试化合物接触,以检测新的小分子调节的蛋白质/蛋白质相互作用。例如,所述方法将化合物鉴定为能够与E3连接酶底物结合亚基诱饵相互作用,并且与这样的诱饵复合,与E3连接酶底物结合亚基的底物或新底物相互作用的化合物。例如,所述方法将化合物鉴定为能够与E3连接酶底物结合亚单位相互作用并调节第二蛋白质(例如,猎物,例如但不限于E3连接酶底物结合亚基的底物或新底物)的募集和/或泛素化和/或降解的化合物。
在一些实施方案中,本发明的诱饵蛋白是E3连接酶底物结合亚基。E3连接酶(也称为泛素连接酶)是一类多样化的蛋白质,它们在功能上识别靶蛋白并介导靶蛋白和泛素部分之间的共价连接。它们在泛素化过程中提供靶特异性和独特性。E3连接酶募集已加载有泛素的E2泛素结合酶,识别靶蛋白,并协助或直接催化泛素从E2转移至蛋白质底物。
可以使用本领域已知的任何E3连接酶进行本发明中描述的方法。在一些实施方案中,本发明的E3连接酶包括与E2-泛素硫酯和底物蛋白相互作用并催化泛素有效转移至靶蛋白的赖氨酸残基(聚泛素链起始)或生长链中的泛素的蛋白质。在一些实施方案中,本发明方法包括E3连接酶的亚基。根据本发明的E3连接酶亚基可以是功能性E3连接酶或功能性E3连接酶的非功能部分。
在一些实施方案中,本发明的E3连接酶或其亚基选自小脑蛋白(CRBN)和冯·希佩尔-林道(VHL)。
在一个实施方案中,本发明的E3连接酶是小脑蛋白(cereblon)或其亚基。
在一些实施方案中,支架蛋白是受损的DNA结合蛋白1(DDB1)、滞蛋白-4A(CUL4A)、滞蛋白调节剂1(ROC1)、SKP1、SKP1相互作用伴侣(SKIP2)、含有β-转导蛋白重复序列的蛋白(β-TrCP)、双微体4蛋白(MDM4)、X连锁凋亡抑制剂(XIAP)、DDB1和CUL4相关因子15(DCAF15)和WD重复序列结构域12(WDR12)或其亚基。
在一些实施方案中,本发明方法允许鉴定新的相互作用伴侣,例如,与化合物结合的蛋白质的底物或新底物,所述蛋白质具有三个色氨酸残基的笼,所述色氨酸残基例如经由氢结合能够与所述化合物的戊二酰亚胺环相互作用。在一些实施方案中,相互作用伴侣,例如,底物和/或新底物,具有表面β-发夹环,所述表面β-发夹环任选地在转角的顶点处具有三个主链氢键受体的排列,随后是甘氨酸残基。在一些实施方案中,相互作用伴侣,例如,底物和/或新底物,具有降解决定子基序(参见,Meszaros等人Sci Signal 2017:10,470,将其全部内容通过引用并入本文)。
在一些实施方案中,诱饵是具有三个色氨酸残基的笼的蛋白质,所述色氨酸残基能够例如经由氢结合与所述化合物(例如,免疫调节药物或免疫调节酰亚胺药物(IMiD))的戊二酰亚胺环相互作用。
在一些实施方案中,猎物,例如,底物和/或新底物,具有表面β-发夹环,所述表面β-发夹环任选地在转角的顶点处具有三个主链氢键受体的排列,随后是甘氨酸残基。在一些实施方案中,猎物,例如,底物和/或新底物,具有降解决定子基序(参见,Meszaros等人Sci Signal 2017:10,470,将其全部内容通过引用并入本文)。
在各种实施方案中,所述公开的方法鉴定了通过小分子与猎物蛋白或诱饵结合介导的蛋白质/蛋白质相互作用。在一些实施方案中,所述方法进一步包括引入与猎物蛋白或诱饵蛋白结合的小分子。在一些实施方案中,分子相互作用是通过小分子与猎物蛋白或诱饵蛋白结合介导的蛋白质/蛋白质相互作用。
在一些实施方案中,分子相互作用是通过小分子与猎物蛋白或诱饵蛋白结合介导的两种或更多种蛋白质/蛋白质相互作用。在一个实施方案中,小分子与诱饵蛋白结合,并且这种结合引起诱饵蛋白发生变化,使得它在与所述小分子结合后能够与猎物蛋白结合。例如,在一个实施方案中,小分子与诱饵蛋白的结合引起诱饵蛋白的构象变化,例如,诱饵蛋白上的结合位点可以变得对于猎物蛋白是可及的,以便与所述诱饵蛋白结合。在另一个实施方案中,小分子与诱饵蛋白的结合使诱饵蛋白内的疏水结合位点打开或暴露,使得猎物蛋白可以与诱饵蛋白的疏水结合位点结合。
在其他实施方案中,小分子与猎物蛋白结合,并且这种结合引起猎物蛋白的变化,使得它现在可以与诱饵蛋白相互作用/结合。在一些实施方案中,小分子与猎物蛋白的结合引起猎物蛋白的构象变化,使得猎物蛋白上的结合位点变得对于诱饵蛋白是可及的,这样它可以与猎物蛋白结合。在其他实施方案中,小分子与与猎物蛋白的结合使猎物蛋白内的疏水结合位点打开或暴露,使得诱饵蛋白可以与猎物蛋白的疏水结合位点相互作用。
仍然在其他实施方案中,本发明方法包括不与诱饵蛋白或猎物蛋白结合但与诱饵蛋白和猎物蛋白之间的复合物结合的小分子。例如,在诱饵蛋白和猎物蛋白之间的相互作用可以重新组织或创建小分子的结合位点。在一些实施方案中,小分子结合位点存在于诱饵蛋白中并且在诱饵蛋白和猎物蛋白之间形成复合物时暴露。在其他实施方案中,小分子结合位点存在于与猎物蛋白中并且在诱饵蛋白和猎物蛋白之间形成复合物时暴露。在一些实施方案中,在诱饵蛋白和猎物蛋白之间的相互作用暴露了现有的小分子结合位点或诱导了小分子结合位点的形成。
在一些实施方案中,由小分子与猎物蛋白或诱饵蛋白的结合介导的蛋白质/蛋白质相互作用是猎物蛋白或诱饵蛋白与小分子之间在蛋白质/蛋白质界面处或在蛋不白质内的直接结合。例如,在一个实施方案中,小分子可以与诱饵蛋白直接结合,形成诱饵蛋白-小分子复合物。在另一个实施方案中,小分子可以与猎物蛋白直接结合,形成猎物蛋白-小分子复合物。
本发明还设想了分子相互作用,其中小分子、猎物和诱饵蛋白同时相互作用。例如,在一个实施方案中,小分子与诱饵蛋白和猎物蛋白两者直接结合。在一些实施方案中,由小分子与猎物蛋白或诱饵蛋白的结合介导的蛋白质/蛋白质相互作用是由猎物蛋白或诱饵蛋白的蛋白质表面的变构修饰介导的。在一些实施方案中,由小分子与诱饵蛋白的结合介导的蛋白质/蛋白质相互作用是由诱饵蛋白的蛋白质表面的变构修饰介导的。
在一些实施方案中,小分子诱导了诱饵蛋白的疏水表面的暴露,从而允许与猎物蛋白相互作用。在一些实施方案中,小分子诱导了猎物蛋白的疏水表面的暴露,从而允许与诱饵蛋白相互作用。
在一些实施方案中,小分子是分子胶。分子胶是在一些情况下促进蛋白质的非天然结合以产生治疗效果的分子。在一些实施方案中,分子胶是其中两个小分子通过接头连接在一起的分子。例如,在实施方案中,本发明化合物是具有与CRBN、VHL和FKBP之一相互作用的化合物的杂合配体。
在其他实施方案中,分子胶是一种小分子,其没有任何将所述小分子与另一小分子连接的接头。在一些实施方案中,分子相互作用是复合物形成。在一些实施方案中,分子相互作用是小分子/蛋白质相互作用。
在一些实施方案中,小分子或化合物是免疫调节剂。在一些实施方案中,所述化合物是谷氨酸的衍生物,其包含戊二酰亚胺环,和任选地,邻苯二甲酰亚胺环。在一些实施方案中,邻苯二甲酰亚胺环是化学修饰的。在一些实施方案中,谷氨酸的衍生物可以是具有根据本公开的实施方案的特性的合成衍生物。在一些实施方案中,所述化合物是称为免疫调节药物或免疫调节酰亚胺药物(IMiD)的化合物类别的成员。在实施方案中,所述化合物含有IMiD样戊二酰亚胺环,但另外在化学结构上不同并且与CRBN中的戊二酰胺-IMiD(CRBN中的IMiD结合口袋)结合相同的小分子结合口袋。在实施方案中,所述化合物不含戊二酰胺环并且可以结合IMiD口袋中的CRBN。在实施方案中,所述化合物结合CRBN,但后者不在IMiD口袋中。在实施方案中,IMiD口袋包含在CRBN的CULT(未知活性的小脑蛋白结构域、结合细胞配体和沙利度胺)结构域中,参见PDB条目4TZ4、5FQD、5HXB、5V3O、6H0F和6H0G以及PLoSComput Biol.2015年1月;11(1):e1004023.,各自通过引用完整并入本文。
在一些实施方案中,所述化合物是沙利度胺、来那度胺、泊马度胺、CC-220、CC-122、CC-885,或其衍生物、类似物、对映体或对映体的混合物,或其药学上可接受的盐、溶剂化物、水合物、共晶体、包合物或多晶型物。
在一些实施方案中,所述化合物是阿伐度胺、恩多米特、伊贝度胺、来那度胺、米丁度胺、泊马度胺和沙利度胺,或其衍生物、类似物、对映体或对映体的混合物,或其药学上可接受的盐、溶剂化物、水合物、共晶体、包合物或多晶型物。
在各种实施方案中,所述第一受体和第二受体是相同的。在各种实施方案中,所述第一受体和第二受体是不同的。
在一些实施方案中,配体结合结构域来源于细胞因子受体。在一些实施方案中,配体结合结构域来源于1型细胞因子受体(CR)。在其他实施方案中,配体结合结构域来源于促红细胞生成素受体(EpoR)或瘦素受体(LR)。在一些实施方案中,跨膜结构域和细胞质结构域来源于鼠瘦素受体。
在一些实施方案中,诱饵对于第一受体和/或第二受体片段是异源的。在一些实施方案中,细胞质结构域包含JAK结合位点。在一些实施方案中,细胞质结构域包含糖蛋白130(gp130)。在一些实施方案中,受体片段包含糖蛋白130(gp130)。在一些实施方案中,STAT选自STAT1或STAT3。
在一些实施方案中,减少或消除STAT募集的突变针对一个或多个酪氨酸磷酸化位点。在一些实施方案中,跨膜和细胞质结构域来源于鼠瘦素受体,并且所述突变位于位置Y985、Y1077和Y1138中的一个或多个。在一些实施方案中,跨膜和细胞质结构域来源于鼠瘦素受体,并且所述突变为Y985F、Y1077F和Y1138F。在一些实施方案中,跨膜和细胞质结构域具有与鼠瘦素受体的Y985F、Y1077F和Y1138F功能等同的突变。
在一些实施方案中,提供了跨膜结构域的缺失,条件是保留JAK结合。
鼠瘦素受体的氨基酸序列如下:
在一些实施方案中,来源于鼠瘦素受体的结构域是鼠瘦素受体序列的氨基酸839-1162。
在一些实施方案中,猎物蛋白包含核输出序列(NES)。例如,在实施方案中,猎物蛋白是核蛋白并且NES确保它在胞质溶胶中是可用的(即,如果适用的话,与诱饵接触)。因而,在实施方案中,即使在存在强的核定位信号时,NES信号也有助于将猎物多肽保持在细胞质中,从而促进与诱饵蛋白的相互作用。
在一些实施方案中,NES具有1-4个疏水残基。在一些实施方案中,疏水残基是亮氨酸。在一些实施方案中,NES具有序列LxxxLxxLxL,其中L是疏水残基,并且x是任何其他氨基酸。在一些实施方案中,NES具有序列LxxxLxxLxL,其中L是亮氨酸,并且x是任何其他氨基酸。
在一些实施方案中,NES包含cAMP依赖性蛋白激酶的热稳定抑制剂的氨基酸37-46,其已被证明超越强的核定位信号(Wiley等人,(1999),J.Biol.Chem.274:6381-6387,将其全部内容通过引用并入本文)。
在一些实施方案中,在蛋白酶体抑制剂的存在下监测或检测在诱饵蛋白、小分子和猎物蛋白或其组合之间的相互作用。在一个实施方案中,所述方法包括向细胞提供蛋白酶体抑制剂。在一些实施方案中,在猎物蛋白与包含E3连接酶组分的诱饵蛋白相互作用后被修饰的情况下,蛋白酶体抑制剂抑制猎物蛋白的潜在降解。用于本文公开的方法中的蛋白酶体抑制剂可以选自卡非佐米(Kyprolis)、硼替佐米(Velcade)、伊沙佐米(Ninlaro)和马里佐米。在一个实施方案中,蛋白酶体抑制剂是硼替佐米(Velcade)。
在各种实施方案中,本发明方法鉴定了新的分子相互作用。在各种实施方案中,本发明方法鉴定了新的蛋白质/蛋白质相互作用。在各种实施方案中,本发明方法鉴定了通过小分子与猎物蛋白或诱饵蛋白结合介导的新的蛋白质/蛋白质相互作用。
在各种实施方案中,本发明方法鉴定了分子相互作用而不需要使用杂合配体(或小分子或化合物)或其中两个小分子实体通过接头连接在一起的配体。在实施方案中,所述小分子是单一化学实体。在实施方案中,所述小分子不具有接头。
在实施方案中,小分子仅与诱饵或猎物蛋白之一直接相互作用。在实施方案中,小分子直接与诱饵和/或猎物蛋白相互作用但仅见于存在诱饵或猎物蛋白的情况,例如小分子直接与猎物蛋白相互作用但仅见于存在诱饵蛋白的情况,或小分子直接与诱饵蛋白相互作用但仅见于存在猎物蛋白的情况,或小分子直接与诱饵或猎物蛋白相互作用但仅见于存在诱饵或猎物蛋白的情况。
在一些实施方案中,本发明方法适用于VHL作为E3连接酶底物结合诱饵蛋白的用途。与CRBN相似,VHL是E3连接酶的底物结合亚基。因此,与作为诱饵的E3连接酶有关的所有实施方案同样适用于VHL作为诱饵。
在实施方案中,本发明方法适用于使用FKBP12蛋白或这个家族的成员(例如FK506结合蛋白)而不是E3连接酶作为诱饵(因此,与E3连接酶作为诱饵有关的所有实施方案同样适用于FKBP12蛋白或这个家族的成员作为诱饵)。
已知FKBP12与免疫抑制剂分子他克莫司(FK506)结合。在实施方案中,小分子是FK506或其衍生物、类似物、对映体或对映体的混合物,或其药学上可接受的盐、溶剂化物、水合物、共晶体、包合物或多晶型物。
通过以下非限制性实施例进一步描述本发明。
在实施方案中,提供了一种用于检测分子相互作用的方法,所述方法包括:(a)提供包含配体依赖性嵌合受体的细胞,所述受体包含:(i)来源于第一受体的配体结合结构域的细胞外部分和(ii)第二受体的跨膜和细胞质结构域和与其融合的细胞内诱饵蛋白,其中所述第二受体的跨膜和/或细胞质结构域包含减少或消除STAT(信号转导和转录激活因子)募集的突变;(b)表达与细胞中的受体片段融合的猎物蛋白,所述受体片段包含功能性STAT募集位点;和(c)检测指示分子相互作用的信号,其中所述诱饵蛋白是FK506结合蛋白(FKBP)。
在实施方案中,在猎物蛋白和诱饵蛋白之间的相互作用引起与诱饵蛋白融合的受体片段募集到跨膜嵌合受体蛋白,从而恢复STAT分子的配体依赖性跨膜嵌合受体信号传导和激活。
在实施方案中,所述细胞包含STAT反应性报告基因。
在实施方案中,激活的STAT分子迁移至细胞核并诱导STAT反应性报告基因的转录,所述报告基因信号允许检测分子相互作用。
在实施方案中,FK506结合蛋白(FKBP)选自FKBP12、FKBP38和FKBP52。
在实施方案中,所述方法进一步包括引入与猎物蛋白和/或诱饵蛋白结合的小分子。
在实施方案中,分子相互作用是通过小分子与猎物蛋白或诱饵蛋白结合介导的蛋白质/蛋白质相互作用。
在实施方案中,分子相互作用是通过小分子与猎物蛋白或诱饵蛋白结合介导的两种或更多种蛋白质/蛋白质相互作用。
在实施方案中,由小分子与猎物蛋白或诱饵蛋白的结合介导的蛋白质/蛋白质相互作用是猎物蛋白或诱饵蛋白与小分子之间在蛋白质/蛋白质界面处的直接结合。
在实施方案中,由小分子与猎物蛋白或诱饵蛋白的结合介导的蛋白质/蛋白质相互作用是由诱饵蛋白的蛋白质表面的变构修饰介导的。
在实施方案中,小分子诱导了诱饵蛋白的疏水表面的暴露,从而允许与猎物蛋白相互作用。
在实施方案中,小分子是分子胶。
在实施方案中,分子相互作用是复合物形成。
在实施方案中,分子相互作用是小分子/蛋白质相互作用。
在实施方案中,所述第一受体和第二受体是相同的。
在实施方案中,所述第一受体和第二受体是不同的。
在实施方案中,所述第一受体和/或第二受体是多聚化受体。
在实施方案中,配体结合结构域来源于细胞因子受体。
在实施方案中,配体结合结构域来源于1型细胞因子受体(CR)。
在实施方案中,配体结合结构域来源于促红细胞生成素受体(EpoR)或瘦素受体(LR)。
在实施方案中,跨膜结构域和细胞质结构域来源于鼠瘦素受体(LR)。
在实施方案中,诱饵对于第一受体和/或第二受体片段是异源的。
在实施方案中,细胞质结构域包含JAK结合位点并且/或者受体片段包含gp130。
在实施方案中,STAT选自STAT1或STAT3。
在实施方案中,减少或消除STAT募集的突变针对一个或多个酪氨酸磷酸化位点。
在实施方案中,跨膜和细胞质结构域来源于鼠瘦素受体(LR),并且所述突变位于位置Y985、Y1077和Y1138中的一个或多个。
在实施方案中,跨膜和细胞质结构域来源于鼠瘦素受体(LR),并且所述突变为Y985F、Y1077F和Y1138F。
在实施方案中,跨膜和细胞质结构域具有与鼠瘦素受体(LR)的Y985F、Y1077F和Y1138F功能等同的突变。
在实施方案中,猎物蛋白包含核输出序列(NES)。
在实施方案中,NES具有1-4个疏水残基。
在实施方案中,疏水残基是亮氨酸。
在实施方案中,NES具有序列LxxxLxxLxL,其中L是疏水残基,并且x是任何其他氨基酸。
在实施方案中,NES具有序列LxxxLxxLxL,其中L是亮氨酸,并且x是任何其他氨基酸。
在实施方案中,诱饵在与猎物蛋白相互作用之前与化合物接触。
在实施方案中,化合物选自FK506(他克莫司)、雷帕霉素(西罗莫司)和环孢素A(CsA)或其衍生物或类似物或与FK506(他克莫司)、雷帕霉素(西罗莫司)和环孢素A(CsA)或其衍生物或类似物结合相同的FKBP诱饵结合位点的化合物,并且所述结合为竞争方式。
在实施方案中,所述方法鉴定了通过小分子与猎物蛋白或诱饵蛋白结合介导的新的蛋白质/蛋白质相互作用。
实施例
实施例1:用于检测分子胶诱导的CRBN底物相互作用的MAPPIT衍生测定配置的评价
为了鉴定配体诱导的CRBN底物或新底物,我们在这里使用MAPPIT测定的衍生物,应用描述于Lemmens等人“MAPPIT,a mammalian two-hybrid method for in-celldetection of protein-protein interactions,”Methods Mol Biol.2015;1278:447-55的程序。传统的MAPPIT测定已用于监测蛋白质-蛋白质相互作用。将诱饵蛋白(蛋白A)表达为融合蛋白,其中它与瘦素受体的工程化细胞内受体结构域进行基因融合,其中瘦素受体本身与促红细胞生成素(Epo)受体的细胞外结构域融合。Epo配体与Epo受体成分的结合导致受体相关细胞内JAK2的激活。然而,激活的JAK2不能激活瘦素受体以触发STAT3结合及其磷酸化,因为它的酪氨酸残基通常被激活的JAK2磷酸化而已发生突变。JAK2可磷酸化的STAT3停泊位点的重构是通过蛋白B与蛋白A的相互作用建立的,由此蛋白B与gp130受体的细胞质结构域(现在含有被激活的JAK2激酶识别的适当酪氨酸残基)融合。因而,蛋白A与蛋白B的物理相互作用重构了EPO触发的JAK2-STAT3信号通路激活。可以通过引入STAT3反应性报告基因来监测STAT3的激活,所述报告基因包括萤光素酶编码基因或编码荧光标志物比如GFP或一些其他类型的荧光蛋白(EGFP等)的基因。以这种方式,MAPPIT测定法提供了一种通用测定法来评估完整细胞中的这种重组蛋白质-蛋白质相互作用。
在这个实施例1中,我们使用了我们专门开发的用于确定CRBN-配体诱导的蛋白质相互作用的MAPPIT测定法的衍生物,即使用特定的CRBN诱饵蛋白并测定蛋白质复合物形成的配体依赖性诱导。将CRBN诱饵蛋白与MAPPIT嵌合膜受体表达为融合物,相互作用的靶蛋白与细胞质gp130受体片段融合(gp130-IKZF1(同工型7)、gp130-靶X、gp130-GSPT1(结构域2+3)或gp130-GSPT2)。我们评价了这种MAPPIT衍生测定法,用于检测一组已知的诱导这些底物募集到CRBN的IMiD(沙利度胺,THL;来那度胺,LEN;泊马度胺,POM;CC-122;CC-220;CC-885)。
用编码CRBN嵌合受体融合物的质粒(pSEL-CRBN)、编码MAPPIT gp130融合物(gp130-IKZF1(同工型7)、gp130-靶X、gp130-GSPT1(结构域2+3)或gp130-GSPT2)的质粒和编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)转染HEK293T细胞,如所述(Lievens,等人″Array MAPPIT:high-throughput interactome analysis inmammalian cells.″Journal of Proteome Research 8.2(2009):877-886)。融合了每个测试的靶蛋白的全尺寸蛋白,其中使用同工型7的IKZF1和其中使用内部子结构域的GSPT1的情况除外。在本实施例中应用的MAPPIT受体融合物由遗传上与瘦素受体的细胞质结构域连锁的感兴趣的蛋白质(CRBN)组成,所述瘦素受体的细胞质结构域本身与促红细胞生成素(EPO)受体的细胞外结构域融合。细胞外EPO受体结构域可以与细胞外瘦素受体结构域(如实施例2中所用)互换使用,以促进受体/受体相关的JAK2活化(分别用EPO或瘦素)。在转染之后24小时,用促红细胞生成素(EPO)处理细胞,同时不用或用指定剂量的测试化合物。在测试化合物处理之后24小时,使用带有Ensight酶标仪(PERKIN ELMER LIFE SCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。数据点描绘了来自EPO+测试化合物处理的细胞与仅EPO处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条形代表标准偏差。使用GRAPHPAD PRISM软件中的4-参数非线性回归拟合曲线。图2A-L中显示的数据表明,MAPPIT募集测定法能够重现已知的相互作用、IMiD特异性(例如仅通过CC-885募集GSPT1和GSPT2)和效力趋势。
实施例2:用于检测IMiD诱导的底物募集的替代性CRBN MAPPIT衍生受体构建体的比较
在这个实施例2中,在实施例1中应用的测定设置与相似的MAPPIT衍生测定配置并排测试,其中使用了替代性CRBN嵌合受体融合构建体。如实施例1中已经提到的,替代性受体融合物是可用的,其中EPO细胞外结构域被替换为瘦素受体的细胞外结构域,导致所述测定系统被瘦素而不是EPO激活。在当前实施例中,用编码CRBN的质粒转染HEK293T细胞,所述质粒栓系到MAPPIT受体融合物上,所述融合物含有EPO受体细胞外结构域(pSEL-CRBN;如实施例1)或瘦素受体细胞外结构域(pCLG-CRBN)。如图3A-D中的卡通图指示,除了细胞外结构域外,这些构建体在嵌合受体的细胞内构型方面也不同。在pSEL-CRBN构建体的情况下,融合物含有整个工程化瘦素受体细胞内结构域,而在pCLG-CRBN构建体中,瘦素受体的一小部分用于包含JAK2募集位点,并且另外的Gly-Gly-Ser铰链被置于这个结构域和与其融合的CRBN诱饵蛋白之间。另外,用编码与部分gp130结构域融合的感兴趣的底物(IKZF1同工型1、IKZF1同工型7、GSPT1同工型1或GSPT1结构域2+3)的质粒和编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)共转染HEK293T细胞,如所述(Lievens等人″Array MAPPIT:high-throughput interactome analysis in mammalian cells.″Journalof Proteome Research 8.2(2009):877-886)。在IKZF1(同工型1)gP130融合物的情况下,应用了两种不同的构建体,其中gp130融合到IKZF1的N端或C端。在转染之后24小时,用EPO(在基于pSEL-CRBN的测定法的情况下)或瘦素(对于基于pCLG-CRBN的测定法)在不用或用指定剂量的测试化合物(CC-220或CC-885)的情况下处理细胞。在测试化合物处理之后24小时,使用带有Ensight酶标仪(PERKIN ELMER LIFE SCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。数据点描绘了来自EPO或瘦素+测试化合物处理的细胞与仅EPO或瘦素处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条形代表标准偏差。在图3A-D中提供的数据表明,两种替代性MAPPIT受体融合物都能够检测分子胶依赖性新底物与CRBN的相互作用。
实施例3:使用DDB1 MAPPIT-衍生受体融合构建体检测CRBN化合物诱导的底物相互作用
由于使用CRBN诱饵的未融合版本测试化合物诱导的CRBN-底物相互作用可能是有利的,我们开发了一种MAPPIT衍生测定法,其中DDB1与MAPPIT嵌合受体构建体而不是CRBN融合。DDB1是衔接蛋白,其将CRBN与核心E3泛素连接酶复合支架亚基CUL4A或CUL4B(滞蛋白4A或滞蛋白4B)连接。用编码栓系到含有EPO受体细胞外结构域的MAPPIT受体融合物的DDB1的质粒(pSEL-DDB1)、编码融合到部分gp130结构域的CRBN底物蛋白(IKZF1同工型7或也用于实施例1中的未公开的靶蛋白X)的质粒和编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)转染HEK293T细胞,如所述(Lievens等人″ArrayMAPPIT:high-throughput interactome analysis in mammalian cells.″Journal ofProteome Research 8.2(2009):877-886)。另外,还用不同量的未融合的CRBN表达构建体共转染细胞。在转染之后24小时,用EPO处理细胞,同时不用或用指定剂量的来那度胺(LEN)。在测试化合物处理之后24小时,使用带有Ensight酶标仪(PERKIN ELMER LIFESCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。数据点描绘了来自EPO+测试化合物处理的细胞与仅EPO处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条形代表标准偏差。如图4中所示,对于IKZF1和靶X相互作用都获得稳健的来那度胺依赖性MAPPIT信号,但仅见于存在共表达的未融合CRBN的情况,表明该信号是由底物gp130融合蛋白与CRBN的结合介导的。
实施例4:在DDB1共表达时CRBN化合物诱导的底物相互作用的增强检测
由于DDB1衔接蛋白是CRBN E3连接酶复合物的重要组分,将CRBN连接到CUL4A或CUL4B复合支架蛋白,内源性DDB1水平可能在表达CRBN底物募集测定的MAPPIT衍生融合蛋白组分的细胞中受到限制。在这个实施例4中,针对IMiD诱导的在CRBN和IKZF1之间的相互作用评价了DDB1共表达的效果。用编码含有EPO受体细胞外结构域的CRBN MAPPIT受体融合物的质粒(pSEL-DDB1)、编码IKZF1(同工型7)的gp130融合物的质粒和编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)转染HEK293T细胞,如所述(Lievens等人″Array MAPPIT:high-throughput interactome analysis in mammalian cells.″Journal of Proteome Research 8.2(2009):877-886)。另外,在一些测试条件下,另外用未融合的DDB1表达质粒共转染细胞。在转染之后24小时,用EPO处理细胞,同时不用或用指定的IMiD剂量(沙利度胺,THL;来那度胺,LEN;泊马度胺,POM;CC-122;CC-220;CC-885)。在测试化合物处理之后24小时,使用带有Ensight酶标仪(PERKIN ELMER LIFE SCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。数据点描绘了来自EPO+测试化合物处理的细胞与仅EPO处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条形代表标准偏差。在图5中的数据显示,在共表达DDB1的样品中,与该化合物的最大信号相比,在较低的化合物浓度下测试的信号增加,表明DDB1的共表达提高了测定灵敏度。
实施例5:使用DDB1-CRBN MAPPIT嵌合受体融合构建体检测CRBN化合物诱导的底物相互作用
如实施例3和4中讨论的,DDB1是CRBN E3连接酶复合物的关键组分,对于CRBN介导的底物募集和泛素化至关重要。除了实施例3和4中应用的测定配置外,另一种MAPPIT衍生测定设置使用含有DDB1和CRBN的基因融合物的MAPPIT受体构建体。用含有EPO受体细胞外结构域的MAPPIT嵌合受体(pSEL-DDB1-CRBN)生成这样的融合物,并将其应用于这个实施例5中。将这个构建体与编码IKZF1(同工型7)的gp 130融合物的质粒和编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)一起转染到HEK293T细胞中,如所述(Lievens等人″Array MAPPIT:high-throughput interactome analysis in mammaliancells.″Journal of Proteome Research 8.2(2009):877-886)。在转染之后24小时,用EPO处理细胞,同时不用或用指定的IMiD剂量(沙利度胺,THL;来那度胺,LEN;泊马度胺,POM;CC-122;CC-220;CC-885)。在测试化合物处理之后24小时,使用带有Ensight酶标仪(PERKINELMER LIFE SCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。数据点描绘了来自EPO+测试化合物处理的细胞与仅EPO处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条形代表标准偏差。在图6中的数据表明,可以将基因DDB1-CRBN融合物应用于MAPPIT衍生测定法中,以检测CRBN IMiD诱导的底物募集。
实施例6:PROTAC诱导的底物与CRBN的结合的评价
在这个实施例6中,我们评价了由Protac诱导的CRBN底物募集,Protac是由化学栓系到底物结合配体上的CRBN结合配体构成的杂合配体。这里测试的化合物是ARV-825,它是CRBN结合配体和BRD4结合化合物的化学融合物。将实施例2中应用的编码具有EPO受体细胞外结构域(pSEL-CRBN)或瘦素受体细胞外结构域(pCLG-CRBN)的融合构建体的两种替代性的编码MAPPIT衍生的CRBN诱饵受体的质粒与BRD4(同工型3)的gp130融合物和编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)一起共转染到HEK293T细胞中,如所述(Lievens等人″Array MAPPIT:high-throughput interactome analysis inmammalian cells.″Journal of Proteome Research 8.2(2009):877-886)。在转染之后24小时,用EPO(在用pSEL-CRBN转染样品的情况下)或瘦素(对于pCLG-CRBN)处理细胞,同时不用或用指定剂量的ARV-825。在测试化合物处理之后24小时,使用带有Ensight酶标仪(PERKIN ELMER LIFE SCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。数据点描绘了来自EPO或瘦素+测试化合物处理的细胞与仅EPO或瘦素处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条形代表标准偏差。在图7A-B中显示的数据显示了在每个测试的测定配置中明显的剂量依赖性信号增加,表明MAPPIT衍生的CRBN底物募集测定法能够检测由PROTAC型分子诱导的相互作用。
实施例7:化合物诱导的FKBP1A(FKBP12)底物相互作用的检测
在这个实施例中,应用MAPPIT衍生测定法来检测FKBP1A(FKBP12)与MTOR和钙调神经磷酸酶亚基的化合物依赖性相互作用。实验设置根据实施例1中描述的程序,使用编码MAPPIT衍生受体和gp130融合物的以下质粒构建体:将FKBP1A诱饵与含有细胞外EPO受体结构域的MAPPIT嵌合受体构建体(pSEL-FKBP1A)融合,并且将靶蛋白与部分gp130结构域(MTOR FRB结构域或PPP3CA)融合。对于钙调神经磷酸酶相互作用,使用了一种另外的测定设置,其中除了MAPPIT受体和gp130融合物外,共表达了编码钙调神经磷酸酶调节亚基的未融合的PPP3R2表达质粒,因为据报道该调节亚基有助于FK506大环内酯诱导的FKBP1A-钙调神经磷酸酶相互作用。用指定的编码受体和gp130的质粒以及编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)转染HEK293T细胞,如所述(Lievens,等人″Array MAPPIT:high-throughput interactome analysis in mammalian cells.″Journalof Proteome Research 8.2(2009):877-886)。在转染之后24小时,用EPO处理细胞,同时不用或用指定剂量的测试化合物(用于MTOR募集的雷帕霉素或依维莫司;用于钙调神经磷酸酶结合的FK506或吡美莫司)。在测试化合物处理之后24小时,使用带有Ensight酶标仪(PERKIN ELMER LIFE SCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。数据点描绘了来自EPO+测试化合物处理的细胞与仅EPO处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条形代表标准偏差。使用GRAPHPAD PRISM软件中的4-参数非线性回归拟合曲线。在图8A-F中显示的结果表明,MAPPIT衍生测定法使得能够监测化合物诱导的FKBP1A靶结合。在钙调神经磷酸酶募集的情况下,信号强度在PPP3R2调节亚基共表达后显著提高。
实施例8:化合物诱导的VHL底物相互作用的检测
与实施例6类似,我们应用MAPPIT衍生测定法来检测VHL与BRD4的Protac依赖性相互作用。将编码具有EPO受体细胞外结构域(pSEL-VHL)或瘦素受体细胞外结构域(pCLG-VHL)的融合构建体的两种替代性的编码MAPPIT衍生的VHL诱饵受体的质粒与BRD4(同工型3)的gp130融合物和编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)一起共转染到HEK293T细胞中,如所述(Lievens,等人″Array MAPPIT:high-throughput interactome analysis in mammalian cells.″Journal of ProteomeResearch8.2(2009):877-886)。在转染之后24小时,用EPO(在用pSEL-CRBN转染样品的情况下)或瘦素(对于pCLG-CRBN)处理细胞,同时不用或用指定剂量的MZ1(VHL和BRD4配体之间的化学融合物)。在测试化合物处理之后24小时,使用带有Ensight酶标仪(PERKIN ELMERLIFE SCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。数据点描绘了来自EPO或瘦素+测试化合物处理的细胞与仅EPO或瘦素处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条形代表标准偏差。在图9A-B中的图显示了在每个测试的测定配置中明显的剂量依赖性信号增加。
实施例9:用于鉴定诱导IKZF1募集到CRBN的新型分子胶的化合物库筛选
在本实施例中,使用在实施例1中应用的MAPPIT衍生的IKZF1-CRBN募集测定法,以微量滴定板格式筛选由96个IMiD和IMiD样分子胶组成的化合物集合,以鉴定诱导IKZF1募集到CRBN的化合物。用编码栓系到含有EPO受体细胞外结构域的嵌合MAPPIT衍生受体的CRBN诱饵蛋白的融合构建体的质粒(pSEL-CRBN)和gp130-IKZF1(同工型7)融合构建体与编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)共转染HEK293T细胞,如所述(Lievens,等人″Array MAPPIT:high-throughput interactome analysis inmammalian cells.″Journal of Proteome Research 8.2(2009):877-886)。在转染之后24小时,用EPO和化合物(或DMSO作为阴性对照)处理细胞。对每种化合物应用三种浓度(在图10A-C中指示为“低”、“中”和“高”):0.8、4和20μM或0.2、1和5μM,取决于先前评估的化合物的细胞毒性水平,并且每个化合物浓度均以一式二份测试。在化合物处理之后24小时,使用带有Ensight酶标仪(PERKIN ELMERLIFE SCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。在图10A-C(左图)中显示的曲线图描绘了化合物处理的样品和DMSO处理的对照两者的平均原始萤光素酶信号的频率分布,每个曲线图对应于三种测试的化合物浓度之一的数据(低、中、高)。对应于化合物处理的样品的双峰分布的右移部分代表那些具有高于背景的信号并因此诱导IKZF1募集到CRBN的化合物。对于三种测试浓度中的一种或多种展现出高于背景的报告信号的三种这样的化合物,萤光素酶信号由线标记(点线、虚线或实线)指示,并显示相应的剂量反应曲线(右图)。使用与初步筛选所使用的相同的测定设置和方案生成这些剂量反应曲线,但现在测试了指定浓度的9点剂量范围。在这里,数据点描绘了来自EPO+测试化合物处理的细胞与仅EPO处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条代表标准偏差,使用GRAPHPAD PRISM软件中的4-参数非线性回归拟合曲线。总之,这个实施例表明,将这里提供的MAPPIT衍生测定法应用于筛选化合物集合,以鉴定诱导底物募集到CRBN的已知的和新的分子胶。图10A-C具体地举例说明了用于诱导IKZF1募集到CRBN的胶的化合物筛选,但可将该方法应用于筛选任何其他潜在的底物。
实施例10:使用MAPPIT衍生的ORF cDNA文库筛选方法鉴定新的分子胶诱导的CRBN底物
为了鉴定配体诱导的CRBN底物或新底物,使用Lievens等人在“Proteome-scalebinary interactomics in human cells.”Molecular&Cellular Proteomics 15.12(2016):3624-3639中描述的程序进行MAPPIT细胞微阵列筛选。简言之,用在先前的实施例1和9中使用的编码栓系到含有EPO受体细胞外结构域的嵌合MAPPIT衍生受体的CRBN诱饵蛋白的融合构建体的相同的CRBN诱饵表达质粒(pSEL-CRBN)转染HEK293T细胞。然后将这些转染的细胞添加到微阵列筛选板,所述板含有覆盖超过15,000个ORF的猎物gp130融合表达质粒集合。微阵列中的每个点都含有不同的gp130-ORF融合表达质粒以及编码STAT3反应性荧光蛋白的报告质粒。降落并附着在这些点上的CRBN诱饵转染的细胞因此也被gp130-ORF猎物质粒和报告质粒转染,导致在每个不同的微阵列点上的细胞中测试不同的CRBN-ORF组合。在转染之后二十四小时,用促红细胞生成素的同时用和不用CRBN配体CC-220(10μM)对细胞进行差异刺激,48小时后读出报告信号(GFP样荧光报告蛋白)。如先前报道,分析荧光强度数据,产生火山图,其中针对相应的细胞簇(X轴)的荧光粒子计数的中值的比率显示了基于每个微阵列细胞簇(Y轴)的积分荧光强度计算的q值,如图11A-B中所示。使用与先前在实施例1和9中应用的相同测定设置和方案,选择四种表现出强信号的ORF cDNA(由图11A-B中的点图上的箭头指示),用于剂量反应确认:将CRBN受体融合质粒(pSEL-CRBN)与相应的gp130-ORF质粒和萤光素酶报告质粒一起共转染到HEK293T细胞中,在转染之后24小时,用EPO同时不用和用指定浓度的CC-220处理细胞,另外24小时后确定萤光素酶活性。剂量-反应曲线代表来自EPO+测试化合物处理的细胞与仅EPO处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条代表标准偏差,使用GRAPHPAD PRISM软件中的4-参数非线性回归拟合曲线。如在这里对于CC-220的情况展示的,这个实施例表明在这里提出的MAPPIT衍生测定法可用于筛选ORF cDNA集合,以鉴定已知的和新的分子胶诱导的CRBN底物。
实施例11:用于鉴定感兴趣的蛋白质的新型配体的杂合配体库筛选
类似于实施例9中描述的方法,在这里使用MAPPIT衍生测定法来筛选化合物库,以便鉴定新型的蛋白质配体。在这里,具体而言,筛选了甲氧苄啶(TMP)-配体杂合分子的集合,用于与感兴趣的蛋白质结合。由于其与DHFR(二氢叶酸还原酶)的紧密结合,TMP可用于将配体作为TMP杂合配体融合分子的一部分锚定到MAPPIT衍生的DHFR受体融合物上,并且像这样将所述配体显示为诱饵(参见图中的卡通图12A-B)。在这个测定设置中,这种DHFR受体融合物与TMP杂合配体和gp130-ORF融合构建体组合成三元复合物,从而产生报告信号。在这个实施例中,筛选了杂合配体库中与雌激素受体(ESR1)结合并且与MDM4(小鼠双微体4)结合的化合物,所述雌激素受体是与乳腺癌有关的核受体和转录因子,所述小鼠双微体4是涉及p53肿瘤抑制因子的调节的重要癌症靶标。这里筛选的化合物集合由320个成员的杂合配体多样性集组成,掺入了TMP-TAM(他莫昔芬),他莫昔芬是已知的ESR1配体。用编码栓系到含有瘦素受体细胞外结构域的嵌合MAPPIT衍生受体的(大肠杆菌)DHFR锚蛋白的融合构建体的质粒(pCLG-DHFR;参见图12A-B中的卡通图)和gp130-ESR1(图12A)或gp130-MDM4(图12B)融合构建体与编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)一起共转染HEK293T细胞,如所述(Lievens,等人″Array MAPPIT:high-throughputinteractome analysis in mammalian cells.″Journal of Proteome Research 8.2(2009):877-886)。在转染之后24小时,用瘦素和化合物(或DMSO作为阴性对照)处理细胞。在化合物处理之后24小时,使用带有Ensight酶标仪(PERKIN ELMER LIFE SCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。在图12A-B(左图)中显示的曲线图描绘了化合物处理的样品和DMSO处理的对照两者的平均原始萤光素酶信号的频率分布。两种分布在很大程度上重叠,但许多化合物表现出高于背景的萤光素酶信号。通过频率曲线上的线标记描绘这些离群值。对于两个示例性筛选中的每一个,在剂量反应分析中确认了一个命中(右图)。这些剂量反应曲线是使用与初步筛选相同的测定设置和方案生成的(除了使用含有突变的瘦素受体细胞内结构域而不是实施例2中描述的Gly-Gly-Ser铰链的替代性DHFR受体锚融合构建体pCLL-DHFR之外),但现在测试指定浓度的9-点剂量范围。在这里,数据点描绘了来自瘦素+测试化合物处理的细胞与仅瘦素处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条代表标准偏差,使用GRAPHPAD PRISM软件中的4-参数非线性回归拟合曲线。在ESR1靶筛选的情况下,确认的命中对应于TMP-TAM,其中TAM是已知的ESR1配体,因此这些数据验证MAPPIT衍生筛选方法。总之,这些实施例表明,可以将这里提供的MAPPIT衍生测定法应用于筛选杂合配体集合,以鉴定已知的和新的配体-靶标相互作用。
实施例12:用MAPPIT衍生测定法鉴定新型杂合配体靶标的基于细胞微阵列的ORFcDNA文库筛选
在这个实施例中,为了鉴定杂合配体诱饵分子的新型靶蛋白,使用Lievens等人在“Proteome-scale binary interactomics in human cells.”Molecular&CellularProteomics 15.12(2016):3624-3639中描述的程序进行类似于实施例10中描述的MAPPIT细胞微阵列筛选。在这里,应用这种筛选方法来鉴定具有强的抗肿瘤表型的未公开化合物的靶标,其中所述化合物的靶标是未知的。为此,合成了杂合配体融合化合物,通过PEG系链将TMP与这种化合物连接。用在先前的实施例11中使用的相同(大肠杆菌)DHFR受体锚融合质粒(pCLG-DHFR)转染HEK293T细胞。然后将这些转染的细胞添加至微阵列筛选板,所述板含有覆盖超过15,000个ORF的猎物gp130融合表达质粒集合。微阵列中的每个点都含有不同的gp130-ORF融合表达质粒以及编码STAT3反应性荧光蛋白的报告质粒。降落并附着在这些点上的DHFR锚融合转染细胞因此也被gp130-ORF猎物质粒和报告质粒转染。在转染之后二十四小时,用瘦素的同时用和不用TMP-化合物杂合配体(5μM终浓度)对细胞进行差异刺激,48小时后读出报告信号(GFP样荧光报告蛋白)。如先前报道,分析荧光强度数据,产生火山图,其中针对相应的细胞簇(X轴)的荧光粒子计数的中值的比率显示了基于每个微阵列细胞簇(Y轴)的积分荧光强度计算的q值,如图13A-B中所示。一种ORF cDNA表现出强信号(由图13A-B中的点图上的箭头指示)并被选择用于剂量反应确认。将DHFR受体融合质粒(pCLG-DHFR)与相应的gp130-ORF质粒和萤光素酶报告质粒一起共转染到HEK293T细胞中,在转染之后24小时,将细胞用瘦素同时不用和用指定浓度的杂合配体处理,并在另外24小时后确定萤光素酶活性。剂量-反应曲线代表来自瘦素+测试化合物处理的细胞与仅瘦素处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条代表标准偏差,使用GRAPHPADPRISM软件中的4-参数非线性回归拟合曲线。这个实施例表明,可以将这里提供的MAPPIT衍生测定法应用于筛选ORF cDNA集合,以鉴定新的配体蛋白靶标。
实施例13:雷帕霉素诱导的MTOR向FKBP蛋白募集的检测
在这个实施例中,开发了MAPPIT衍生测定法,以监测雷帕霉素诱导的在MTOR与FKBP蛋白家族成员特别是FKBP1A(FKBP12)、FKBP3、FKBP4和FKBP5之间的结合。如图14中指示,将FKBP cDNA克隆为含有EPO受体细胞外结构域的MAPPIT受体融合物(pSEL-FKBPx),而将MTOR(FRB结构域)克隆为gp130融合物。用FKBP受体融合构建体的任何一种与gp130-MTOR融合质粒和编码STAT3反应性萤光素酶的报告质粒(pXP2d2-rPAPI-萤光素酶报告质粒)一起共转染HEK293T细胞,如所述(Lievens,等人″Array MAPPIT:high-throughputinteractome analysis in mammalian cells.″Journal of Proteome Research 8.2(2009):877-886)。在转染之后24小时,用EPO处理细胞,同时不用或用指定剂量的雷帕霉素。在测试化合物处理之后24小时,使用带有Ensight酶标仪(PERKIN ELMER LIFESCIENCES,Waltham,MA)的萤光素酶测定系统试剂盒(PROMEGA,Madison,WI)测量萤光素酶活性。数据点描绘了来自EPO素+测试化合物处理的细胞与仅EPO或瘦素处理的细胞的一式三份样品的平均萤光素酶活性的倍数诱导。误差条形代表标准偏差。如所示,对于每个FKBP-MTOR相互作用,可以获得雷帕霉素诱导的报告信号,正如文献中先前报道的那样。
序列表
<110> 奥里尼斯生物科学股份有限公司;奥里尼斯生物科学私人有限公司(OrionisBiosciences, Inc.
Orionis Biosciences BV)
<120> 新型降解相关相互作用的检测
<130> ORN-064PC/114384-5064
<150> US 62/949,026
<151> 2019-12-17
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 1162
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成聚合物.
<400> 1
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Ser Val Val Lys Ala Ser Val Phe Arg Gln Leu Gly Val Asn Trp Asp
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Glu Pro Leu Pro Lys Asn Pro Phe Lys Asn Tyr Asp Ser Lys Val His
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Claims (80)
1.一种用于检测分子相互作用的方法,所述方法包括:
(a)提供包含配体依赖性嵌合受体的细胞,所述受体包含:
(i)来源于第一受体的配体结合结构域的细胞外部分,和
(ii)第二受体的跨膜和细胞质结构域和与其融合的细胞内诱饵蛋白,其中所述第二受体的跨膜和/或细胞质结构域包含减少或消除STAT(信号转导和转录激活因子)募集的突变;
(b)表达与细胞中的受体片段融合的猎物蛋白,所述受体片段包含功能性STAT募集位点;并且
(c)检测指示分子相互作用的信号,
其中,所述诱饵蛋白是E3连接酶底物结合亚基。
2.一种用于检测分子相互作用的方法,所述方法包括:
(a)提供包含配体依赖性嵌合受体的细胞,所述受体包含:
(i)来源于第一受体的配体结合结构域的细胞外部分,和
(ii)第二受体的跨膜和细胞质结构域和与其融合的细胞内诱饵支架蛋白,其中所述第二受体的跨膜和/或细胞质结构域包含减少或消除STAT(信号转导和转录激活因子)募集的突变;
(b)表达与细胞中的受体片段融合的猎物蛋白,所述受体片段包含功能性STAT募集位点;并且
(c)检测指示分子相互作用的信号,
其中,与所述第二受体的跨膜和/细胞质结构域融合的诱饵支架蛋白与诱饵蛋白结合,所述诱饵蛋白是E3连接酶底物结合亚基。
3.根据权利要求1或2所述的方法,其中在所述猎物蛋白和诱饵蛋白之间的相互作用引起与所述诱饵蛋白融合的受体片段募集到跨膜嵌合受体蛋白,从而恢复STAT分子的配体依赖性跨膜嵌合受体信号传导和激活。
4.根据权利要求3所述的方法,其中所述细胞包含STAT反应性报告基因。
5.根据权利要求4所述的方法,其中所述激活的STAT分子迁移至细胞核并诱导STAT反应性报告基因的转录,所述报告基因信号允许检测分子相互作用。
6.根据权利要求1-5中任一项所述的方法,其中所述E3连接酶底物结合亚基选自小脑蛋白(CRBN)和冯·希佩尔-林道(VHL)。
7.根据权利要求2-6中任一项所述的方法,其中所述支架蛋白选自受损的DNA结合蛋白1(DDB1)、滞蛋白-4A(CUL4A)、滞蛋白调节剂1(ROC1)、SKIP1、SKP1相互作用伴侣(SKIP2)、含有β-转导蛋白重复序列的蛋白(β-TrCP)、双微体4蛋白(MDM4)、X连锁凋亡抑制剂(XIAP)、DDB1和CUL4相关因子15(DCAF15)和WD重复序列结构域12(WDR12)。
8.根据上述权利要求中任一项所述的方法,其中所述方法进一步包括引入与所述猎物蛋白和/或诱饵蛋白结合的小分子。
9.根据权利要求8所述的方法,其中所述分子相互作用是通过小分子与所述猎物蛋白或诱饵蛋白结合介导的蛋白质/蛋白质相互作用。
10.根据上述权利要求中任一项所述的方法,其中所述分子相互作用是通过所述小分子与所述猎物蛋白或诱饵蛋白结合介导的两种或更多种蛋白质/蛋白质相互作用。
11.根据权利要求8-10中任一项所述的方法,其中由所述小分子与所述猎物蛋白或诱饵蛋白的结合介导的蛋白质/蛋白质相互作用是在所述猎物蛋白或诱饵蛋白与所述小分子之间在蛋白质/蛋白质界面处的直接结合。
12.根据权利要求8-10中任一项所述的方法,其中由所述小分子与所述猎物蛋白或诱饵蛋白的结合介导的蛋白质/蛋白质相互作用是由所述诱饵蛋白的蛋白质表面的变构修饰介导的。
13.根据权利要求12所述的方法,其中所述小分子诱导了所述诱饵蛋白的疏水表面的暴露,从而允许与所述猎物蛋白相互作用。
14.根据权利要求8-13中任一项所述的方法,其中所述小分子是分子胶。
15.根据权利要求1或2所述的方法,其中所述分子相互作用是复合物形成。
16.根据权利要求1或2所述的方法,其中所述分子相互作用是小分子/蛋白质相互作用。
17.根据权利要求1-16中任一项所述的方法,其中所述第一受体和第二受体是相同的。
18.根据权利要求1-16中任一项所述的方法,其中所述第一受体和第二受体是不同的。
19.根据权利要求1-18中任一项所述的方法,其中所述第一受体和/或第二受体是多聚化受体。
20.根据权利要求1-19中任一项所述的方法,其中所述配体结合结构域来源于细胞因子受体。
21.根据权利要求1-20中任一项所述的方法,其中所述配体结合结构域来源于1型细胞因子受体(CR)。
22.根据权利要求1-20中任一项所述的方法,其中所述配体结合结构域来源于促红细胞生成素受体(EpoR)或瘦素受体(LR)。
23.根据权利要求22所述的方法,其中所述跨膜结构域和细胞质结构域来源于鼠瘦素受体(LR)。
24.根据权利要求1-23中任一项所述的方法,其中所述诱饵对于所述第一受体和/或第二受体片段是异源的。
25.根据权利要求1-24中任一项所述的方法,其中所述细胞质结构域包含JAK结合位点并且/或者所述受体片段包含gp130。
26.根据权利要求1-25中任一项所述的方法,其中所述STAT选自STAT1或STAT3。
27.根据权利要求1-26中任一项所述的方法,其中所述减少或消除STAT募集的突变针对一个或多个酪氨酸磷酸化位点。
28.根据权利要求1-27中任一项所述的方法,其中所述跨膜和细胞质结构域来源于鼠瘦素受体(LR),并且所述突变位于位置Y985、Y1077和Y1138中的一个或多个。
29.根据权利要求1-28中任一项所述的方法,其中所述跨膜和细胞质结构域来源于鼠瘦素受体(LR),并且所述突变为Y985F、Y1077F和Y1138F。
30.根据权利要求1-29中任一项所述的方法,其中所述跨膜和细胞质结构域具有与鼠瘦素受体(LR)的Y985F、Y1077F和Y1138F功能等同的突变。
31.根据权利要求1-30中任一项所述的方法,其中所述猎物蛋白包含核输出序列(NES)。
32.根据权利要求31所述的方法,其中所述NES具有1-4个疏水残基。
33.根据权利要求32所述的方法,其中所述疏水残基是亮氨酸。
34.根据权利要求32-33中任一项所述的方法,其中所述NES具有序列LxxxLxxLxL,其中L是疏水残基,并且x是任何其他氨基酸。
35.根据权利要求32-34中任一项所述的方法,其中所述NES具有序列LxxxLxxLxL,其中L是亮氨酸,并且x是任何其他氨基酸。
36.根据上述权利要求中任一项所述的方法,其中所述诱饵在与所述猎物蛋白相互作用之前与化合物接触。
37.根据权利要求36所述的方法,其中所述化合物包含戊二酰亚胺环和邻苯二甲酰亚胺环。
38.根据权利要求37所述的方法,其中所述化合物选自沙利度胺、来那度胺、泊马度胺、CC-220、CC-122、CC-885或其衍生物或类似物,或与沙利度胺、来那度胺、泊马度胺、CC-220、CC-122、CC-885或其衍生物或类似物结合相同的CRBN诱饵结合位点的化合物,并且所述结合为竞争方式。
39.根据上述权利要求中任一项所述的方法,其中所述方法鉴定:
通过所述小分子与所述猎物蛋白或诱饵蛋白结合介导的新的蛋白质/蛋白质相互作用,或
诱导、介导或稳定化蛋白质-蛋白质相互作用的小分子化合物,其包含所述猎物蛋白和诱饵蛋白,所述小分子化合物任选地是分子胶或杂合配体。
40.一种用于检测分子相互作用的方法,所述方法包括:
(a)提供包含配体依赖性嵌合受体的细胞,所述受体包含:
(i)来源于第一受体的配体结合结构域的细胞外部分,和
(ii)第二受体的跨膜和细胞质结构域和与其融合的细胞内诱饵蛋白,其中所述第二受体的跨膜和/或细胞质结构域包含减少或消除STAT(信号转导和转录激活因子)募集的突变;
(b)表达与细胞中的受体片段融合的猎物蛋白,所述受体片段包含功能性STAT募集位点;并且
(c)检测指示分子相互作用的信号,
其中,所述诱饵蛋白是FK506结合蛋白(FKBP)。
41.根据权利要求40所述的方法,其中在所述猎物蛋白和诱饵蛋白之间的相互作用引起与所述诱饵蛋白融合的受体片段募集到跨膜嵌合受体蛋白,从而恢复STAT分子的配体依赖性跨膜嵌合受体信号传导和激活。
42.根据权利要求41所述的方法,其中所述细胞包含STAT反应性报告基因。
43.根据权利要求42所述的方法,其中所述激活的STAT分子迁移至细胞核并诱导STAT反应性报告基因的转录,所述报告基因信号允许检测分子相互作用。
44.根据权利要求40-43中任一项所述的方法,其中所述FK506结合蛋白(FKBP)选自FKBP12、FKBP38和FKBP52。
45.根据权利要求40-44中任一项所述的方法,其中所述方法进一步包括引入与所述猎物蛋白和/或诱饵蛋白结合的小分子。
46.根据权利要求45所述的方法,其中所述分子相互作用是通过小分子与所述猎物蛋白或诱饵蛋白结合介导的蛋白质/蛋白质相互作用。
47.根据权利要求40-46中任一项所述的方法,其中所述分子相互作用是通过所述小分子与所述猎物蛋白或诱饵蛋白结合介导的两种或更多种蛋白质/蛋白质相互作用。
48.根据权利要求45-47中任一项所述的方法,其中由所述小分子与所述猎物蛋白或诱饵蛋白的结合介导的蛋白质/蛋白质相互作用是在所述猎物蛋白或诱饵蛋白与所述小分子之间在蛋白质/蛋白质界面处的直接结合。
49.根据权利要求45-47中任一项所述的方法,其中由所述小分子与所述猎物蛋白或诱饵蛋白的结合介导的蛋白质/蛋白质相互作用是由所述诱饵蛋白的蛋白质表面的变构修饰介导的。
50.根据权利要求49所述的方法,其中所述小分子诱导了所述诱饵蛋白的疏水表面的暴露,从而允许与所述猎物蛋白相互作用。
51.根据权利要求45-50中任一项所述的方法,其中所述小分子是分子胶。
52.根据权利要求40或41所述的方法,其中所述分子相互作用是复合物形成。
53.根据权利要求40或41所述的方法,其中所述分子相互作用是小分子/蛋白质相互作用。
54.根据权利要求40-53中任一项所述的方法,其中所述第一受体和第二受体是相同的。
55.根据权利要求40-54中任一项所述的方法,其中所述第一受体和第二受体是不同的。
56.根据权利要求40-55中任一项所述的方法,其中所述第一受体和/或第二受体是多聚化受体。
57.根据权利要求40-56中任一项所述的方法,其中所述配体结合结构域来源于细胞因子受体。
58.根据权利要求40-57中任一项所述的方法,其中所述配体结合结构域来源于1型细胞因子受体(CR)。
59.根据权利要求40-57中任一项所述的方法,其中所述配体结合结构域来源于促红细胞生成素受体(EpoR)或瘦素受体(LR)。
60.根据权利要求59所述的方法,其中所述跨膜结构域和细胞质结构域来源于鼠瘦素受体(LR)。
61.根据权利要求40-60中任一项所述的方法,其中所述诱饵对于所述第一受体和/或第二受体片段是异源的。
62.根据权利要求40-61中任一项所述的方法,其中所述细胞质结构域包含JAK结合位点并且/或者所述受体片段包含gp130。
63.根据权利要求40-62中任一项所述的方法,其中所述STAT选自STAT1或STAT3。
64.根据权利要求40-63中任一项所述的方法,其中所述减少或消除STAT募集的突变针对一个或多个酪氨酸磷酸化位点。
65.根据权利要求40-64中任一项所述的方法,其中所述跨膜和细胞质结构域来源于鼠瘦素受体(LR),并且所述突变位于位置Y985、Y1077和Y1138中的一个或多个。
66.根据权利要求40-65中任一项所述的方法,其中所述跨膜和细胞质结构域来源于鼠瘦素受体(LR),并且所述突变为Y985F、Y1077F和Y1138F。
67.根据权利要求40-66中任一项所述的方法,其中所述跨膜和细胞质结构域具有与鼠瘦素受体(LR)的Y985F、Y1077F和Y1138F功能等同的突变。
68.根据权利要求40-67中任一项所述的方法,其中所述猎物蛋白包含核输出序列(NES)。
69.根据权利要求68所述的方法,其中所述NES具有1-4个疏水残基。
70.根据权利要求69所述的方法,其中所述疏水残基是亮氨酸。
71.根据权利要求69-70中任一项所述的方法,其中所述NES具有序列LxxxLxxLxL,其中L是疏水残基,并且x是任何其他氨基酸。
72.根据权利要求69-71中任一项所述的方法,其中所述NES具有序列LxxxLxxLxL,其中L是亮氨酸,并且x是任何其他氨基酸。
73.根据权利要求40-72中任一项所述的方法,其中所述诱饵在与所述猎物蛋白相互作用之前与化合物接触。
74.根据权利要求73所述的方法,其中所述化合物选自FK506(他克莫司)、雷帕霉素(西罗莫司)和环孢素A(CsA)或其衍生物或类似物或与FK506(他克莫司)、雷帕霉素(西罗莫司)和环孢素A(CsA)或其衍生物或类似物结合相同的FKBP诱饵结合位点的化合物,并且所述结合为竞争方式。
75.根据权利要求40-74中任一项所述的方法,其中所述方法鉴定通过所述小分子与所述猎物蛋白或诱饵蛋白结合介导的新的蛋白质/蛋白质相互作用。
76.一种用于检测分子相互作用的方法,所述方法包括:
(a)提供包含配体依赖性嵌合受体的细胞,所述受体包含:
(i)来源于第一受体的配体结合结构域的细胞外部分,和
(ii)第二受体的跨膜和细胞质结构域和与其融合的细胞内诱饵蛋白,其中所述第二受体的跨膜和/或细胞质结构域包含减少或消除STAT(信号转导和转录激活因子)募集的突变,
其中,所述诱饵蛋白是小脑蛋白(CRBN)或FK506结合蛋白(FKBP);
(b)表达与细胞中的受体片段融合的猎物蛋白,所述受体片段包含功能性STAT募集位点;
(c)检测指示分子相互作用的信号,并且
(d)引入与所述猎物蛋白和/或诱饵蛋白结合的小分子,
其中所述分子相互作用是通过所述小分子与所述猎物蛋白或诱饵蛋白结合介导的蛋白质/蛋白质相互作用。
77.根据权利要求76所述的方法,其中由所述小分子与所述猎物蛋白或诱饵蛋白的结合介导的蛋白质/蛋白质相互作用是由所述诱饵蛋白的蛋白质表面的变构修饰介导的。
78.根据权利要求77所述的方法,其中所述小分子诱导了所述诱饵蛋白的疏水表面的暴露,从而允许与所述猎物蛋白相互作用。
79.根据权利要求78所述的方法,其中所述小分子是分子胶化合物或杂合配体。
80.根据权利要求78所述的方法,其中所述方法鉴定:
通过所述小分子与所述猎物蛋白或诱饵蛋白结合介导的新的蛋白质/蛋白质相互作用,或
诱导、介导或稳定化蛋白质-蛋白质相互作用的小分子化合物,其包含所述猎物蛋白和诱饵蛋白,所述小分子化合物任选地是分子胶或杂合配体。
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