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

项目摘要/摘要 胶质母细胞瘤是最常见和最致命的原发脑肿瘤，中位生存期为9.7个月。 目前的护理治疗标准包括手术、化疗和放射治疗的组合，但仅限于 将中位生存期提高到14个月。发现GBM的治疗方法面临的挑战包括识别 药物靶点和发现可透过血脑屏障(BBB)的治疗药物。为了迎接挑战， 我们已经确定小泛素相关修饰物1(SUMO1)是一种癌蛋白，可以驱动自我更新和 骨髓间充质干细胞的致瘤作用。我们设计了基于GBM细胞的SUMO1实验，筛选了化合物 库，并鉴定了命中的化合物是第一个小分子 在GBM细胞中诱导SUMO1泛素化和降解的降解物。构效关系(SAR) 围绕HIT衍生类似物的研究已经产生了三种具有更高效力的先导化合物支架 和极佳的血脑屏障渗透性。使用GBM干细胞丰富的神经球和衍生的异种移植物，我们 已经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Lead系列，以确定更强大的、 口服生物利用度和BBB渗透性的SUMO1降解剂，将具有临床前的有效性、安全性和 预测其药代动力学特性，可为临床治疗基底膜提供充分的探索。要做到这一点 目标，我们将利用我们的计算化学技术来辅助设计新的化合物 通过对目标1中的铅系列进行化学修饰来实现血脑屏障的渗透性和类药物性质。 化合物将在我们建立的化合物测试漏斗中进行合理的设计、合成和评估 它们在SUMO1降解中的活性和目标选择性。符合我们成功标准的化合物将 根据体外溶解度、渗透性、吸收、分布、新陈代谢和排泄评估进行选择 并优先考虑针对GBM干细胞丰富的神经球的抗癌活性。在《目标2》中，领先的 从Aim 1研究中选择的化合物将被评估其药代动力学特性，以确定 口服生物利用度和血脑屏障通透性。选定的化合物将被评估为体内靶标结合 以及对患者来源的异种GBM模型的治疗效果。优化的先导化合物 从AIM 2的研究中挑选出来的药物将接受毒理学、安全性药理学和口服制剂的评估 目标3.本项目的里程碑是筛选优化的先导化合物(S)以进入临床前阶段 开发阶段，研究性新药使能研究和治疗GMB患者的第一阶段试验。

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.