Development of BBB-permeable SUMO1 small molecule degraders for glioblastoma therapy.

开发用于胶质母细胞瘤治疗的 BBB 渗透性 SUMO1 小分子降解剂。

基本信息

批准号：
10420361
负责人：
CHUNHAI Charlie HAO
金额：
$ 47.46万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10420361
关键词：
ABCB1 gene Adverse effects Antineoplastic Agents Binding Binding Proteins Biological Assay Biological Availability Biological Products Brain Brain Neoplasms CRISPR/Cas technology CUL1 gene Cells Chemicals Chemotherapy and/or radiation Clinical Management Clinical Treatment Clinical Trials Complex Development Diagnosis Dose Drug Kinetics Drug Targeting Excretory function Formulation Glioblastoma Guidelines Human In Vitro Knock-out Lead Libraries Malignant Neoplasms Metabolic Metabolism Modeling Modification Molecular National Cancer Institute Neurosphere Oncoproteins Operative Surgical Procedures Oral Patients Permeability Pharmaceutical Preparations Pharmacology Pharmacology Study Pharmacotherapy Phase Physiological Primary Brain Neoplasms Property Proteins Proteomics Rodent Safety Small Ubiquitin-Related Modifier Proteins Solubility Specificity Structure-Activity Relationship Technology Testing Therapeutic Toxic effect Toxicology Treatment Efficacy Ubiquitin Ubiquitination United States National Institutes of Health Xenograft procedure absorption analog anticancer activity base blood-brain barrier permeabilization chemotherapy computational chemistry counterscreen curative treatments design drug discovery genome-wide improved in vivo lead optimization lead series monolayer novel novel anticancer drug novel therapeutics patient derived xenograft model phase I trial preclinical development preclinical efficacy preclinical safety preclinical toxicity rational design recruit scaffold screening self-renewal small molecule standard of care stem cells success synergism temozolomide tumorigenesis ubiquitin-protein ligase

项目摘要

Project Summary/Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor with the median survival of 9.7 months. The current standard of care treatment involves a combination of surgery, chemotherapy and radiation but only improve the median survival up to 14 months. Challenges in discovery of therapeutics for GBM include identifying drug targets and discovering therapeutics that are blood brain barrier (BBB) permeable. To meet the challenges, we have identified small ubiquitin-related modifier 1 (SUMO1) as an oncoprotein that drives the self-renewal and tumorigenesis of GBM stem cells. We have designed GBM cell-based SUMO1 assay, screened the compounds library provided by the National Cancer Institute, and identified the hit compound as the first small molecule degrader that induces SUMO1 ubiquitination and degradation in GBM cells. Structure-activity relationship (SAR) studies around the hit-derived analogs have generated three scaffolds of lead compounds with improved potency and an excellent BBB permeability. Using GBM stem cell-enriched neurospheres and derived xenografts, we have shown that the lead compounds are more effective in treatment of GBM than the standard chemotherapy temozolomide (TMZ). In this R01 project, we will optimize our lead series with the aim of identifying more potent, orally bioavailable and BBB-permeable SUMO1 degraders that will have the preclinical efficacy, safety, and pharmacokinetic properties predicting it be enable full exploration in clinical treatment of GBM. To achieve this objective, we will leverage our computational chemistry technology to assist the design of novel compounds with BBB permeability and drug-like properties through chemical modifications of our lead series in Aim 1. Each of compounds will be rationally designed, synthesized and assessed in our established compound testing funnel for their activity and target selectivity in SUMO1 degradation. Compounds that meet our criteria for success will be selected for in vitro solubility, permeability, absorption, distribution, metabolism, and excretion assessment and prioritized for the anticancer activity against GBM stem cell-enriched neurospheres. In Aim 2, the leading compounds selected from the studies of Aim 1 will be evaluated for their pharmacokinetic properties to determine oral bioavailability and BBB permeability. Selected compounds will be assessed for in vivo target engagement and therapeutic efficacy in treatment of patient derived xenograft GBM models. The optimized lead compounds selected from the studies in Aim 2 will be evaluated for their toxicology, safety pharmacology and oral formulation in Aim 3. The milestone of this project is to select optimized lead compound(s) for advancement into preclinical development phase, investigative new drug-enabling studies and phase I trials in treatment of GMB patients.

项目摘要/摘要胶质母细胞瘤（GBM）是最常见，最致命的原发性脑肿瘤，中位生存期为9.7个月。当前的护理水平治疗标准涉及手术，化学疗法和放疗的组合，但仅改善最多14个月的中位生存期。 GBM发现治疗剂的挑战包括识别药物靶标并发现可渗透血脑屏障（BBB）的治疗剂。为了应对挑战，我们已经将与泛素相关的小修饰剂1（SUMO1）确定为一种驱动自我更新和的癌蛋白 GBM干细胞的肿瘤发生。我们设计了基于GBM细胞的SUMO1分析，筛选了化合物由国家癌症研究所提供的图书馆，并确定该命中型化合物是第一个小分子诱导SUMO1泛素化和降解的DEGRADER在GBM细胞中。结构活性关系（SAR）围绕杀手类似物的研究产生了三种铅化合物的脚手架，具有提高的效力以及出色的BBB渗透性。使用富含GBM干细胞的神经球和衍生的异种移植物，我们已经表明，铅化合物比标准化疗更有效地治疗GBM Temozolomide（TMZ）。在这个R01项目中，我们将优化我们的领先系列，以确定更有效的，口服生物可利用和BBB可渗透的SUMO1降解器，具有临床前功效，安全性和药代动力学特性预测它可以在GBM的临床治疗中进行全面探索。实现这一目标目的，我们将利用我们的计算化学技术来协助设计新颖化合物的设计 BBB渗透性和类似药物的特性，通过我们的铅系列的化学修饰在AIM 1中。化合物将在我们既定的化合物测试漏斗中合理设计，合成和评估用于SUMO1降解中的活性和靶向选择性。符合我们成功标准的化合物将选择用于体外溶解度，渗透率，吸收，分布，代谢和排泄评估并优先考虑针对GBM干细胞富集神经球的抗癌活性。在AIM 2中，领先将评估从AIM 1研究中选择的化合物的药代动力学特性，以确定口服生物利用度和BBB渗透性。将评估选定的化合物的体内目标参与和治疗患者衍生异种移植GBM模型的治疗功效。优化的铅化合物从AIM 2中选择的毒理学，安全药理学和口服制剂将进行评估在AIM 3中。该项目的里程碑是选择优化的铅化合物以发展为临床前开发阶段，调查性新药物研究和I期治疗GMB患者的试验。