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.
蛋白质水解靶向嵌合体(PROTAC)是事件驱动的双功能小分子,同时 接合E3泛素连接酶和目的蛋白质(POI)。POI-PROTAC-间三元复合物的形成 E3连接酶,导致E3连接酶介导的POI泛素化和随后的26 S 蛋白酶体PROTAC技术的下一个创新是诱导肿瘤特异性蛋白 降解在肿瘤细胞中选择性诱导降解的PROTAC可能会改善 由于脱靶细胞毒性降低而具有治疗效用。目前,E3连接酶最常被劫持用于 PROTAC介导的POI降解、von Hippel-Lindau、Cereblon和小鼠双微体2同源物, 在癌组织和未转化的组织中表达。因此,新的E3连接酶募集元件(E3 RE) 使E3连接酶与肿瘤特异性表达结合,以赋予肿瘤特异性。I型 黑色素瘤抗原基因(法师)家族蛋白是癌症睾丸抗原,其表达限于 男性生殖细胞,但可以在癌症中重新表达。MAGE-A3结合TRIM 28,一种广泛表达的 具有E3连接酶活性的蛋白,以形成致癌肿瘤特异性E3连接酶复合物。一个PROTAC包含一个 MAGE-A3 E3 RE可能能够募集MAGE-A3/TRIM 28并在肿瘤特异性细胞中诱导蛋白质降解。 方式法师蛋白通过保守的法师同源结构域结合其同源E3连接酶和底物 (MHD)。使用Schrödinger Glide对接软件,我们筛选了超过60,000种化合物, MAGE-A3 MHD的解析结构,以通过计算机识别预测破坏MAGE-A3 MHD的配体。 底物结合我们已经确定了一个子集的铅样化合物使用固有的色氨酸荧光 并且目前正在通过正交生物物理测定如等温量热法来证实这些发现, 以及各种基于NMR的策略。对真正的MAGE-A3粘合剂的结构-活性关系研究将 然后进行改进溶解度、增加亲和力和鉴定用于接头连接的潜在载体 在随后的PROTAC开发中。一旦开发出紧密结合的MAGE-A3配体,我们将 合成基于MAGE-A3-HaloPROTAC并测试它们在MAGE-A3- 依赖的方式。随后,我们将进一步测试募集MAGE-A3/TRIM 28 E3连接酶的效用 通过靶向含溴结构域蛋白4(BRD 4)用于基于法师的PROTAC介导的复合物 降解诱导BRD 4的肿瘤特异性降解和诱导肿瘤特异性细胞凋亡 我们的MAGE-A3为基础的PROTAC的方式将进行评估。总的来说,该项目将决定法师- A3/TRIM 28 E3连接酶复合物诱导肿瘤特异性蛋白降解。此外,开发新的 E3 RE将有助于激发对其他E3连接酶的新型E3 RE的鉴定,从而大大扩展 适用于PROTAC技术的E3连接酶的数量。此外,该项目期间创建的PROTAC 可以作为肿瘤特异性治疗的未来发展的起点。

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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