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Proteasomal recruiters of PAX3-FOXO1 Designed via Sequence-Based Generative Models

通过基于序列的生成模型设计的 PAX3-FOXO1 蛋白酶体招募剂

基本信息

批准号：
10826068
负责人：
CHRISTOPHER M COUNTER
金额：
$ 15.77万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10826068
关键词：
26S proteasome Acceleration Affinity Algorithm Design Algorithms Alveolar Rhabdomyosarcoma Amino Acid Sequence Amino Acids Architecture Awareness Base Sequence Benchmarking Binding Binding Proteins Binding Sites Cause of Death Cell Line Cell model Cells Child Childhood Chimeric Proteins Chromatin Code Data Databases Development Disease FOXO1A gene Funding Fusion Oncogene Proteins Gene Expression Generations Glues Glycine Goals High-Risk Cancer Language Learning Ligands Malignant Childhood Neoplasm Malignant Neoplasms Mass Spectrum Analysis Medicine Modeling Molecular Oncogenic Oncoproteins Outcome PAX3 gene Pathogenicity Pathway interactions Peptides Phage Display Pharmaceutical Preparations Protac Protein Engineering Proteins Reporter Rhabdomyosarcoma Risk Serine Skeletal Muscle Sodium Chloride Soft tissue sarcoma Structure System Technology Testing Therapeutic Toxic effect Training Translations Ubiquitin United States Validation Western Blotting Work Yeasts clinically relevant deep learning model design effective therapy high risk population histogenesis improved in vitro Model in vitro testing in vivo in vivo Model model design multicatalytic endopeptidase complex new technology novel protein aminoacid sequence protein degradation protein protein interaction public health relevance recruit screening small molecule transcription factor tumorigenic ubiquitin-protein ligase vector

项目摘要

Abstract Fusion-positive alveolar rhabdomyosarcoma (FP-ARMS), one of the most fatal childhood cancers, is primarily dependent on the PAX3-FOXO1 fusion oncoprotein, a chimeric transcription factor that hijacks normal gene expression and chromatin state. The five-year survival for children with PAX3-FOXO1-positive ARMS is ~30% and <10% when metastatic. PAX3-FOXO1 is largely considered an undruggable protein, with no small molecule developed to bind and inhibit its activity. Recently, we have developed novel algorithms to design specific peptides that selectively bind and degrade pathogenic proteins, including classically “undruggable” transcription factors and fusion oncoproteins. In this proposal, we will ensemble our state-of-the-art generative models to de novo design high-affinity peptide-guided degraders selective to PAX3-FOXO1 (and not PAX3 or FOXO1) and demonstrate degradation within in vitro models of FP-ARMS. The outcomes of this work will motivate downstream in vivo studies and accelerate protein-targeting medicines for FP-ARMS.

摘要融合阳性腺泡状横纹肌肉瘤（FP-ARMS）是最致命的儿童癌症之一，依赖于PAX 3-FOXO 1融合癌蛋白，一种劫持正常基因的嵌合转录因子表达和染色质状态。PAX 3-FOXO 1阳性ARMS儿童的5年生存率约为30% 转移性时<10%。PAX 3-FOXO 1在很大程度上被认为是一种不可药用的蛋白质，没有小分子开发来结合和抑制其活性。最近，我们开发了新的算法来设计特定的选择性结合和降解致病蛋白质的肽，包括经典的“非药物性”转录因子和融合癌蛋白。在这个提议中，我们将集成我们最先进的生成模型来实现 novo design对PAX 3-FOXO 1（而非PAX 3或FOXO 1）具有选择性的高亲和力肽导向降解剂，证明在FP-ARMS体外模型中降解。这项工作的成果将激励下游体内研究和加速蛋白靶向药物FP-ARMS。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A method to culture human alveolar rhabdomyosarcoma cell lines as rhabdospheres demonstrates an enrichment in stemness and Notch signaling.

DOI：
10.1242/bio.050211
发表时间：
2021-02-09
期刊：
Biology open
影响因子：
2.4
作者：
Slemmons KK;Deel MD;Lin YT;Oristian KM;Kuprasertkul N;Genadry KC;Chen PH;Chi JT;Linardic CM
通讯作者：
Linardic CM

Expression of oncogenic HRAS in human Rh28 and RMS-YM rhabdomyosarcoma cells leads to oncogene-induced senescence.