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：
10580075
负责人：
CHUNHAI Charlie HAO
金额：
$ 46.54万
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/10580075
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 Cytoplasm 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 Proliferating 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 Western Blotting Xenograft procedure absorption analog anticancer activity 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.

项目概要/摘要胶质母细胞瘤 (GBM) 是最常见和致命的原发性脑肿瘤，中位生存期为 9.7 个月。目前的护理治疗标准包括手术、化疗和放疗的组合，但仅将中位生存期提高至 14 个月。 GBM 治疗方法发现的挑战包括确定药物靶点并发现血脑屏障 (BBB) 可渗透的治疗方法。为了应对挑战，我们已经确定小泛素相关修饰物 1 (SUMO1) 是一种癌蛋白，可驱动自我更新和 GBM 干细胞的肿瘤发生。我们设计了基于GBM细胞的SUMO1测定法，筛选了化合物由美国国家癌症研究所提供的库，并鉴定出该化合物为第一个小分子诱导 GBM 细胞中 SUMO1 泛素化和降解的降解剂。构效关系（SAR）围绕命中衍生的类似物的研究已经产生了三种具有改进效力的先导化合物支架和优异的 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，我们已表明先导化合物在治疗 GBM 方面比标准化疗更有效替莫唑胺（TMZ）。在这个 R01 项目中，我们将优化我们的先导系列，旨在识别更有效、口服生物利用度和 BBB 渗透性 SUMO1 降解剂，具有临床前功效、安全性和药代动力学特性预示着它能够在 GBM 的临床治疗中进行充分的探索。为了实现这一目标目标，我们将利用我们的计算化学技术来协助设计新型化合物通过对目标 1 中的先导系列进行化学修饰，实现 BBB 渗透性和类药特性。化合物将在我们建立的化合物测试漏斗中进行合理设计、合成和评估表彰其在 SUMO1 降解中的活性和靶标选择性。符合我们成功标准的化合物将选择用于体外溶解度、渗透性、吸收、分布、代谢和排泄评估并优先考虑针对富含 GBM 干细胞的神经球的抗癌活性。在目标 2 中，领先的将评估从目标 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血脑屏障渗透性。将评估所选化合物的体内靶标参与度以及患者来源的异种移植 GBM 模型的治疗效果。优化的先导化合物从目标 2 中选择的研究将对其毒理学、安全药理学和口服制剂进行评估目标 3。该项目的里程碑是选择优化的先导化合物以推进临床前研究开发阶段、调查性新药启用研究和治疗 GMB 患者的 I 期试验。