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: 10424788
• 负责人: Eric Sebastian Fischer
• 金额: $ 28.47万
• 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/10424788
• 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/antagonist; 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.!

用小分子抑制剂靶向致癌激酶现已成为治疗癌症的经过充分验证的范例 癌症类型和大约 25 种针对靶点的药物，如 ALK、EGFR、BCR-ABL、BTK、C-KIT、b- RAF 和 PDFGRβ 现已在临床常规使用。不幸的是，除了对 BCR-ABL 的长期反应 慢性粒细胞白血病的抑制剂，对其他抑制剂的耐药性通常在使用后 1-2 年出现。 初步成功响应。此外，一些肿瘤依赖于激酶的支架功能，而不是依赖于激酶的支架功能。 酶激酶活性，从而使抑制剂无效。例如，假激酶 Her3 是 与 EGFR 和 Her2 的专性异二聚化伙伴，但不需要其激酶活性。在这里我们 建议探索一种全新的方法来使用小分子消除激酶功能 可以选择性促进感兴趣的激酶靶点降解的分子。特别是，我们将 利用最近描述的方法，涉及开发二价小分子，诱导 感兴趣目标的泛素化和随后的蛋白酶体降解。我们将使用相关配体 沙利度胺，它可以招募 E3 连接酶 CUL4-RBX1-DDB1-CRBN (CRL4CRBN)，我们称之为“选择性” 降解剂（也称为 PROTAC 或 degronimids）。我们开发了强大的质谱分析法- 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 该策略确定了两个经过充分验证的目标，并且非常有效 降级：BTK 和 FLT3。我们已经为 FLT3 和 BTK 开发了优秀的原型降解器，将在 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 确定了一个具有治疗意义的靶标，HER3，它是一种假激酶（催化失活），但可作为 EGFR 和 HER2 的关键二聚化伙伴，因此代表了一个独特的靶向机会 通过降解。本次拨款申请的目标是开发优化的小分子 BTK、FLT3 和 HER3 的降解剂，并了解其生化和结构基础 他们的作用机制。表现出对这些激酶依赖性的经过充分验证的细胞模型将被 用于研究激酶抑制和降解之间的细胞反应有何不同。！