Degrading therapeutically important kinases using small molecules

使用小分子降解治疗上重要的激酶

• 批准号: 10311055
• 负责人: Eric Sebastian Fischer
• 金额: $ 22.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311055
• 关键词: Address; Apoptosis; Applications Grants; Binding; Biochemical; Biological Assay; Cell Cycle; Cell model; Cells; Chemistry; Chronic Myeloid Leukemia; Clinical; Collection; Complement; Complex; Credentialing; Degradation Pathway; Dependence; Development; Dimerization; Drug resistance; ERBB2 gene; ERBB3 gene; Epidermal Growth Factor Receptor; Exhibits; FLT3 gene; Genetic Diseases; Genetic Transcription; Goals; Grant; Heterodimerization; Ligands; Ligase; Malignant Neoplasms; Mass Spectrum Analysis; Oncogenic; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Proteins; Proteomics; Proto-Oncogene Protein c-kit; RBX1 gene; Research; Resistance; Signal Pathway; Signal Transduction; Structure; System; Thalidomide; Therapeutic; Ubiquitination; Work; anticancer treatment; base; bcr-abl Fusion Proteins; cancer cell; cancer therapy; cancer type; clinically relevant; design; in vivo; inhibitor; inhibitor therapy; interest; kinase inhibitor; mutant; novel strategies; novel therapeutics; protein degradation; prototype; recruit; response; scaffold; small molecule; small molecule inhibitor; targeted treatment; tumor; ubiquitin-protein ligase

Targeting of oncogenic kinases with small molecule inhibitors is now a well validated paradigm for treatment of cancer types and approximately 25 drugs directed at targets such as ALK, EGFR, BCR-ABL, BTK, C-KIT, b- RAF and PDFGRβ are now in routine clinical use. Unfortunately, except for long-term responses to BCR-ABL inhibitors in Chronic Myeloid Leukemia, resistance to other inhibitors typically develops 1-2 years after an initially successful response. In addition, some tumors depend on the scaffolding function of a kinase and not on enzymatic kinase activity, thereby rendering inhibitors ineffective. For example the pseudokinase Her3 is an obligate heterodimerization partner with EGFR and Her2 but its kinase activity is not required. Here we propose to explore a fundamentally new approach to abrogating kinase function using small molecules that can selectively promote the degradation of kinase targets of interest. In particular, we will exploit a recently described approach involving the development of bivalent small molecules that induce ubiquitination and subsequent proteasomal degradation of targets of interest. We will use ligands related to thalidomide, which can recruit the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN) that we call `selective degraders' (also known as PROTACs or degronimids). We have developed a powerful mass spectrometry- based proteomics approach that has allowed us to determine which kinases are more susceptible to degradation by this strategy, which has identified two well credentialed targets that are very efficiently degraded: BTK and FLT3. We have developed excellent prototype degraders for FLT3 and BTK which will be further optimized to obtain compounds capable of degrading these targets in vivo. In addition, we have identified a target of therapeutic interest, HER3 that is a pseudokinase (catalytically inactive) but serves as a critical dimerization partner with EGFR and HER2 and therefore represents a unique opportunity for targeting through degradation. The goal of this grant application is to develop optimized small molecule degraders of BTK, FLT3 and HER3 and to understand the biochemical and structural underpinnings of their mechanism of action. Well validated cellular models that exhibit dependencies on these kinases, will be used to investigate how the cellular response differs between kinase inhibition and degradation.!

现在，用小分子抑制剂靶向致癌激酶是一个良好的范式，用于治疗 癌症类型和大约25种针对靶标的药物，例如ALK，EGFR，BCR-ABL，BTK，C-KIT，B- RAF和PDFGRβ现在正在常规临床使用中。不幸的是，除了对BCR-ABL的长期响应 慢性髓样白血病的抑制剂，对其他抑制剂的抗性通常在 最初成功的响应。另外，某些肿瘤取决于激酶的脚手架功能 在酶促激酶活性上，从而使抑制剂无效。例如，假子酶Her3是 与EGFR和HER2的强制性异二聚体合作伙伴，但不需要其激酶活动。我们在这里 提议探索一种从根本上使用小的新方法来消除激酶功能 可以选择性地促进感兴趣的激酶靶标的分子。特别是，我们会 利用一种最近描述的方法，涉及影响影响的小分子 泛素化和随后感兴趣靶标的蛋白酶体降解。我们将使用与 Thalidomide，可以募集E3连接酶Cul4-rbx1-DDB1-CRBN（CRL4CRBN），我们称为“选择性” DEGRADERS的（也称为Protacs或Degronimid）。我们已经开发了强大的质谱 - 基于蛋白质组学的方法使我们能够确定哪些激酶更容易受到影响 该策略的退化，该策略已经确定了两个良好的目标，它们非常有效 退化：BTK和FLT3。我们为FLT3和BTK开发了出色的原型降解器 进一步优化以获得能够在体内降解这些靶标的化合物。此外，我们还有 确定了理论感兴趣的目标，HER3是一种假酶（催化性无活性），但作为一个 与EGFR和HER2的批判性二聚化合作伙伴，因此代表了目标的独特机会 通过退化。该赠款应用的目的是开发优化的小分子 BTK，FLT3和HER3的降级器，并了解生化和结构的基础 他们的作用机理。经过良好验证的细胞模型暴露了对这些激酶的依赖性，将是 用于研究激酶抑制和降解之间的细胞反应如何区别。