UBIQUIBODY PLATFORM FOR TARGETED DEGRADATION OF ONCOGENIC FUSION PROTEINS

用于靶向降解致癌融合蛋白的 Ubiquibody 平台

• 批准号: 10806354
• 负责人: MATHEW BARNETT
• 金额: $ 35.49万
• 依托单位: UBIQUITX, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-27 至 2024-02-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10806354
• 关键词: 3-Dimensional; ANXA5 gene; Acceleration; Amino Acids; Apoptosis; Architecture; Artificial Intelligence; Binding; Biological Assay; Cell Death; Cell Line; Cell Survival; Cell model; Cells; Charge; Chimeric Proteins; Clinical; Code; Collaborations; Collection; DNA; Development; Docking; Encapsulated; Engineering; Ensure; Event; FGFR2 gene; Fee-for-Service Plans; Fibroblast Growth Factor Receptors; Flow Cytometry; Formulation; Future; Genetic; Human; Human Cell Line; In Vitro; Intrahepatic Cholangiocarcinoma; Lead; Lentivirus Vector; Licensing; Link; Lipids; Liver; Liver neoplasms; Luciferases; Mediating; Medicine; Messenger RNA; Modeling; Mus; Mutation; Oncogenic; Organoids; Particle Size; Pathway interactions; Patients; Peptides; Plasmids; Proteins; Protocols documentation; Provider; Reporter; Resistance; Stains; Structure; Surface; Technology; Testing; Therapeutic; Tyrosine Kinase Domain; Ubiquitin; Universities; Western Blotting; Work; clinically relevant; design; drug discovery; in silico; in vivo; inhibitor; interest; multicatalytic endopeptidase complex; novel; overexpression; protein degradation; response; small molecule; transcriptome sequencing; tumor; ubiquitin-protein ligase; vector

UbiquiTx is pioneering a novel class of mRNA therapeutics that potently and selectively degrade targets not historically addressable by small-molecule degraders. Ubiquibodies (uAbs) are protein fusions that can bind to a target of interest and tag it for targeted intracellular degradation via the endogenous ubiquitin-proteasome pathway (UPP). These novel molecules promise to fundamentally transform drug discovery and human medicine by co-opting the UPP to achieve targeted protein degradation. UbiquiTx artificial intelligence-driven discovery platform enables in silico design of thousands of protein targets, accelerating the development of protein degraders across a broad range of clinical indications. In this project, UbiquiTx will design specific uAbs to selectively target and degrade FGFR2 fusions, a common genetic event in patients with intrahepatic cholangiocarcinoma (iCCA). Candidates will be encapsulated within LNP formulations to test delivery to iCCA cells and functional degradation capability. The feasibility of our approach is supported by our previous computation-mediated engineering of effective, peptide-based uAbs, as well as our recent work demonstrating the potential therapeutic benefit of FGFR2 degradation for the treatment of iCCA. Notably, the uAbs designed should be effective even in patients with acquired resistance to small molecule FGFR inhibitors because of secondary mutations in the FGFR tyrosine kinase domain.

Ubiquitx是一类新型mRNA治疗剂的先驱，它可以有效和选择性地降解小分子降解剂历史上无法解决的靶标。泛体（uAb）是蛋白质融合体，其可以结合到感兴趣的靶标并标记它以通过内源性泛素-蛋白酶体途径（UPP）靶向细胞内降解。这些新型分子有望通过选择UPP实现靶向蛋白质降解，从根本上改变药物发现和人类医学。Ubiquitx人工智能驱动的发现平台可以通过计算机设计数千种蛋白质靶点，加速蛋白质降解剂在广泛临床适应症中的开发。在这 Ubiquitx将设计特异性uAb，以选择性靶向和降解FGFR 2融合，这是肝内胆管癌（iCCA）患者的常见遗传事件。候选物将被封装在LNP制剂中，以测试向iCCA细胞的递送和功能降解能力。我们的方法的可行性得到了我们之前有效的基于肽的uAb的计算介导工程的支持，以及我们最近的工作证明了FGFR 2降解对iCCA治疗的潜在治疗益处。值得注意的是，设计的uAb应该是 甚至在由于FGFR酪氨酸激酶结构域中的继发突变而对小分子FGFR抑制剂具有获得性耐药性的患者中也有效。