Developing Tumor-specific PROTACs

开发肿瘤特异性 PROTAC

基本信息

  • 批准号:
    10470405
  • 负责人:
  • 金额:
    $ 37.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-05 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Proteolysis Targeting Chimeras (PROTACs) are event-driven bifunctional small-molecules that simultaneously engage an E3 ubiquitin ligase and a protein of interest (POI). Ternary complex formation between POI-PROTAC- E3 ligase, results in E3-ligase mediated POI ubiquitination and subsequent degradation of the POI by the 26S proteasome. The next innovation for PROTAC technology is the induction of tumor-specific protein degradation. PROTACs that induce degradation selectively in tumor cells would likely have improved therapeutic utility due to decreased off-target cytotoxicity. Currently, the E3 ligases most commonly hijacked for PROTAC-mediated POI degradation, von Hippel-Lindau, Cereblon, and Mouse double minute 2 homolog, are expressed in both cancerous and untransformed tissues. Therefore, new E3 ligase recruiting elements (E3REs) that engage E3 ligases with tumor-specific expression must be developed to impart tumor-specificity. Type I Melanoma Antigen Gene (MAGE) family proteins are cancer testis antigens, whose expression is restricted to the male germ line, but can be re-expressed in cancers. MAGE-A3 binds TRIM28, a ubiquitously expressed protein with E3 ligase activity, to form an oncogenic tumor-specific E3 ligase complex. A PROTAC harboring a MAGE-A3 E3RE may be able to recruit MAGE-A3/TRIM28 and induce protein degradation in a tumor-specific manner. MAGE proteins bind their cognate E3 ligases and substrates via a conserved MAGE homology domain (MHD). Using Schrödinger Glide docking software, we screened >60,000 compounds against the recently resolved structure of the MAGE-A3 MHD to identify ligands in silico that are predicted to disrupt MAGE-A3- substrate binding. We have identified a subset of lead-like compounds using intrinsic tryptophan fluorescence and are currently corroborating these findings via orthogonal biophysical assays such as isothermal calorimetry, and various NMR-based strategies. A structure-activity relationship study on bona-fide MAGE-A3 binders will then be performed to improve solubility, increase affinity, and identify (a) potential vector(s) for linker attachment in subsequent PROTAC development. Once tight-binding MAGE-A3 ligands have been developed, we will synthesize MAGE-A3-based-HaloPROTACs and test their ability to degrade HaloTag7-GFP in a MAGE-A3- dependent manner. Subsequently, we will further test the utility of recruiting MAGE-A3/TRIM28 E3 ligase complex by targeting Bromodomain-containing protein 4 (BRD4) for MAGE based-PROTAC mediated degradation. Induction of tumor-specific degradation of BRD4 and induction of apoptosis in a tumor-specific manner by our MAGE-A3 based-PROTACs will be evaluated. Overall, this project will determine the MAGE- A3/TRIM28 E3 ligase complex induce tumor-specific protein degradation. Additionally, development of a new E3RE will help spark excitement for identification of novel E3REs for other E3 ligases, thereby greatly expanding the number of E3 ligase amenable to the PROTAC technology. Moreover, PROTACs created during this project may serve as the starting point for the future development of a tumor-specific therapy.
蛋白水解靶向嵌合体(PROTAC)是事件驱动的双功能小分子,同时 使用E3泛素连接酶和感兴趣蛋白(POI)。POI-PROTAC-三元络合物的形成 E3连接酶,导致E3连接酶介导的POI泛素化,并随后由26S降解POI 蛋白酶体。PROTAC技术的下一个创新是诱导肿瘤特异性蛋白 退化。选择性地诱导肿瘤细胞降解的PROTAC很可能已经得到了改善 由于靶外细胞毒性降低而产生的治疗效用。目前,E3连接酶最常被劫持用于 PROTAC介导的POI降解、von Hippel-Lindau、Cereblon和小鼠双分钟2同源基因 在癌组织和未转化组织中均有表达。因此,新的E3连接酶招募元件(E3REs) 必须开发具有肿瘤特异性表达的E3连接酶来传递肿瘤特异性。第I类 黑色素瘤抗原基因(MAGE)家族蛋白是肿瘤睾丸抗原,其表达仅限于 雄性生殖系,但可以在癌症中重新表达。MAGE-A3与广泛表达的TRIM28结合 具有E3连接酶活性的蛋白质,形成肿瘤特异性的E3连接酶复合体。一辆PROTAC,里面藏有 MAGE-A3 E3RE可能能够募集MAGE-A3/TRIM28并诱导肿瘤特异的蛋白质降解 举止。MAGE蛋白通过保守的MAGE同源结构域与其同源E3连接酶和底物结合 (MHD)。使用Schrödinger Glide对接软件,我们筛选了6万种化合物与最近的 MAGE-A3 MHD的已解析结构,以确定硅胶中预测会干扰MAGE-A3- 底物结合。我们已经使用本征色氨酸荧光识别了一类铅化合物 目前正在通过等温量热法等正交生物物理测试来证实这些发现, 以及各种基于核磁共振的策略。真正的MAGE-A3结合剂Will的构效关系研究 然后进行以改善溶解性、增加亲和力并鉴定(A)连接接头的潜在载体(S 在随后的PROTAC开发中。一旦紧密结合的MAGE-A3配体被开发出来,我们将 合成基于MAGE-A3-HaloPROTAC并测试其在MAGE-A3-GFP中降解HaloTag7-GFP的能力 依赖的态度。随后,我们将进一步测试招募MAGE-A3/TRIM28 E3连接酶的实用性 靶向含溴结构域蛋白4的MAGE-PROTAC复合物 退化。诱导肿瘤特异性BRD4降解和诱导肿瘤特异性细胞凋亡 我们将评估基于MAGE-A3的PROTAC的方式。总体而言,这个项目将决定法师- A3/TRIM28 E3连接酶复合体诱导肿瘤特异性蛋白降解。此外,开发一种新的 E3RE将有助于激发人们对鉴定其他E3连接酶的新E3RE的兴奋,从而极大地扩展 适用于PROTAC技术的E3连接酶的数量。此外,在该项目期间创建的PROTAC 可作为未来肿瘤特异性治疗方法发展的起点。

项目成果

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CRAIG M CREWS其他文献

CRAIG M CREWS的其他文献

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{{ truncateString('CRAIG M CREWS', 18)}}的其他基金

Developing Tumor-specific PROTACs
开发肿瘤特异性 PROTAC
  • 批准号:
    10244943
  • 财政年份:
    2019
  • 资助金额:
    $ 37.44万
  • 项目类别:
Inducing Proximity: An Emerging Paradigm for New Therapeutic Modalities
诱导接近:新治疗方式的新兴范例
  • 批准号:
    10518541
  • 财政年份:
    2015
  • 资助金额:
    $ 37.44万
  • 项目类别:
Inducing Protein Degradation: A New Pharmaceutical Paradigm
诱导蛋白质降解:新的制药范例
  • 批准号:
    9142301
  • 财政年份:
    2015
  • 资助金额:
    $ 37.44万
  • 项目类别:
Inducing Protein Degradation: A New Pharmaceutical Paradigm
诱导蛋白质降解:新的制药范例
  • 批准号:
    10250394
  • 财政年份:
    2015
  • 资助金额:
    $ 37.44万
  • 项目类别:
KRas Ligand Development
KRas 配体开发
  • 批准号:
    9023184
  • 财政年份:
    2015
  • 资助金额:
    $ 37.44万
  • 项目类别:
Inducing Protein Degradation: A New Pharmaceutical Paradigm
诱导蛋白质降解:新的制药范例
  • 批准号:
    9763483
  • 财政年份:
    2015
  • 资助金额:
    $ 37.44万
  • 项目类别:
Inducing Protein Degradation: A New Pharmaceutical Paradigm
诱导蛋白质降解:新的制药范例
  • 批准号:
    8955987
  • 财政年份:
    2015
  • 资助金额:
    $ 37.44万
  • 项目类别:
Inducing Proximity: An Emerging Paradigm for New Therapeutic Modalities
诱导接近:新治疗方式的新兴范例
  • 批准号:
    10701073
  • 财政年份:
    2015
  • 资助金额:
    $ 37.44万
  • 项目类别:
Towards Mammalian Limb Regeneration
迈向哺乳动物肢体再生
  • 批准号:
    8536848
  • 财政年份:
    2010
  • 资助金额:
    $ 37.44万
  • 项目类别:
Towards Mammalian Limb Regeneration
迈向哺乳动物肢体再生
  • 批准号:
    7994509
  • 财政年份:
    2010
  • 资助金额:
    $ 37.44万
  • 项目类别:

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晚期妊娠维持和抑制早产中cAMP信号活化PR的作用机制研究
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