Development of SUMO1 small molecule degraders as the first-in-class anticancerdrugs for metastatic colorectal cancer

开发 SUMO1 小分子降解剂作为治疗转移性结直肠癌的一流抗癌药物

• 批准号: 10484074
• 负责人: Anita Bellail
• 金额: $ 101.96万
• 依托单位: HB THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484074
• 关键词: 3-Dimensional; Antineoplastic Agents; Binding; Binding Proteins; Biological Assay; Biological Availability; Biological Products; Biopsy; CRISPR/Cas technology; CUL1 gene; Cancer Etiology; Cancer cell line; Canis familiaris; Cell Line; Cells; Cessation of life; Chemicals; Chemistry; Clinical Trials; Clone Cells; Cytochromes; Development; Diagnosis; Disease; Dose; Drug Kinetics; Excretory function; Formulation; Goals; Grant; Human; In Vitro; Knock-out; Large Intestine Carcinoma; Lead; Liver; Lung; Malignant Neoplasms; Mediating; Medical; Metabolic; Metabolism; Modeling; Modification; Mus; Nuclear Magnetic Resonance; Oral; Oral Administration; Organoids; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phase I Clinical Trials; Property; Proteins; Proteomics; Regimen; Rodent; Safety; Series; Small Business Innovation Research Grant; Solid; Solubility; Specificity; Structure-Activity Relationship; Technology; Testing; Therapeutic; Toxicology; Translations; Treatment Efficacy; Ubiquitin; Ubiquitination; Work; Xenograft procedure; absorption; analog; anti-cancer; anticancer activity; base; cancer cell; cancer diagnosis; cell growth; computational chemistry; computerized tools; counterscreen; design; effective therapy; genome-wide; genotoxicity; human disease; improved; in vivo; lead optimization; lead series; metastatic colorectal; novel; novel anticancer drug; novel therapeutics; patient derived xenograft model; preclinical development; preclinical efficacy; preclinical safety; preclinical toxicity; rational design; response; small molecule; solid state; success; therapeutic biomarker; trend; tumorigenesis; ubiquitin ligase; 3-Dimensional; Antineoplastic Agents; Binding; Binding Proteins; Biological Assay; Biological Availability; Biological Products; Biopsy; CRISPR/Cas technology; CUL1 gene; Cancer Etiology; Cancer cell line; Canis familiaris; Cell Line; Cells; Cessation of life; Chemicals; Chemistry; Clinical Trials; Clone Cells; Cytochromes; Development; Diagnosis; Disease; Dose; Drug Kinetics; Excretory function; Formulation; Goals; Grant; Human; In Vitro; Knock-out; Large Intestine Carcinoma; Lead; Liver; Lung; Malignant Neoplasms; Mediating; Medical; Metabolic; Metabolism; Modeling; Modification; Mus; Nuclear Magnetic Resonance; Oral; Oral Administration; Organoids; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phase I Clinical Trials; Property; Proteins; Proteomics; Regimen; Rodent; Safety; Series; Small Business Innovation Research Grant; Solid; Solubility; Specificity; Structure-Activity Relationship; Technology; Testing; Therapeutic; Toxicology; Translations; Treatment Efficacy; Ubiquitin; Ubiquitination; Work; Xenograft procedure; absorption; analog; anti-cancer; anticancer activity; base; cancer cell; cancer diagnosis; cell growth; computational chemistry; computerized tools; counterscreen; design; effective therapy; genome-wide; genotoxicity; human disease; improved; in vivo; lead optimization; lead series; metastatic colorectal; novel; novel anticancer drug; novel therapeutics; patient derived xenograft model; preclinical development; preclinical efficacy; preclinical safety; preclinical toxicity; rational design; response; small molecule; solid state; success; therapeutic biomarker; trend; tumorigenesis; ubiquitin ligase

Project Summary/Abstract Colorectal carcinoma (CRC) is the 4th most diagnosed cancer but the 2nd leading cause of cancer death mainly due to its metastatic disease (mCRC) in the liver and lungs. Currently there is no effective therapy available for patients diagnosed with mCRC. The ultimate goal of this project is to develop small-molecule degraders of small ubiquitin-related modifier 1 (SUMO1) as the first-in-class anticancer drugs for treatment of mCRC therapy. To achieve this goal, we have already identified a hit compound that selectively degrades SUMO1 protein in cancer but not normal cells. Structure-activity relationship (SAR) studies around the hit compound have generated our lead compounds with improved potency and drug-like properties. Using genetically defined CRC cell lines, 3- dimensional (3D) organoids and patient’s derived xenografts (PDXs), we have shown that the lead compounds are more effective in treatment of mCRC than the current standard therapy. Our earlier work has focused on establishing a well-connected testing paradigm with sufficient capacity, including all the required in vitro and in vivo assays that has enabled identification and characterization of the current lead series. In this SBIR Phase II project, we will optimize our lead series with the aim to identify potent, selective and orally bioavailable SUMO1 degrader candidate(s). The candidate(s) will have the necessary preclinical efficacy, safety, and pharmacokinetic properties that predict it be enable full exploration of efficacy and safety in mCRC patients. In particular, Aim 1 will leverage our computational chemistry technology to assist the design of novel compounds through chemical modifications of the lead series. Each compound will be rationally designed, synthesized, and advanced through our established compound testing funnel. First, compounds will be screened using our high-capacity primary, secondary and counter-screen assays for their binding and target selectivity. 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 CRC cell lines and 3D organoids. In Aim 2, the leading compounds selected from the studies of Aim 1 will be evaluated for their pharmacokinetic properties in rodents to determine clearance and oral bioavailability. Selected compound will be further assessed for in vivo target engagement and therapeutic efficacy using our mCRC PDX models after oral administration. Successful compounds will need to demonstrate an in vivo dose response target engagement with an adequate efficacious dose for translation into acceptable predicted human therapeutic dose and regimen. The optimized lead compounds through the studies in Aim 2 will be further evaluated for their toxicology, safety pharmacology, genotoxicity and oral bioavailability in dogs in Aim 3. The milestone of this project is to select the optimized lead compound(s) for advancement into preclinical development phase, investigative new drug-enabling studies and phase I clinical trials in treatment of patients diagnosed with mCRC, a deadly human disease.

项目摘要/摘要 结直肠癌（CRC）是诊断出的第四大癌症，但癌症死亡的第二大原因主要是 由于其转移性疾病（MCRC）在肝脏和肺部。目前尚无有效的疗法 被诊断为MCRC的患者。该项目的最终目标是开发小分子的小分子降解器 泛素相关的修饰剂1（SUMO1）作为治疗MCRC治疗的第一类抗癌药物。到 实现此目标，我们已经确定了一种命中化合物，可有选择地降解癌症中的SUMO1蛋白 但不是正常细胞。围绕热门化合物的结构活性关系（SAR）研究已经产生了我们的 铅化合物具有改善的效力和类似药物的特性。使用一般定义的CRC细胞系，3- 尺寸（3D）类器官和患者的衍生Xenographathics（PDXS），我们已经证明了铅化合物 比当前的标准疗法更有效地治疗MCRC。我们的早期工作重点是 建立具有足够容量的良好连接测试范式，包括所有所需的体外和IN 实现当前铅序列的识别和表征的Vivo Assas。在SBIR II期中 项目，我们将优化我们的领先系列，目的是确定潜力，选择性和口头生物利用SUMO1 DEGRADER候选人。候选人将具有必要的临床前效率，安全性和药代动力学 预测它可以充分探索MCRC患者的效率和安全性的特性。特别是目标1 将利用我们的计算化学技术来通过化学来帮助设计新颖化合物 铅系列的修改。每种化合物将经过合理设计，合成和提出 我们已建立的化合物测试漏斗。首先，将使用我们的大能力主要筛选化合物 次级和反屏幕分析的结合和目标选择性。符合我们标准的化合物 为了成功，将选择用于体外溶解度，渗透率，抽象，分布，代谢和排泄 评估并优先针对CRC细胞系和3D器官的抗癌活性。在AIM 2中 从AIM 1的研究中选择的主要化合物将在其药代动力学特性中评估 啮齿动物确定清除和口服生​​物利用度。选定的化合物将进一步评估体内 口服后使用我们的MCRC PDX模型的目标参与和治疗效率。成功的 化合物将需要表现出体内剂量响应靶向目标，并具有足够的有效效率 剂量以转化为可接受的预测人类治疗剂量和方案。优化的铅 通过AIM 2中研究的化合物将进一步评估其毒理学，安全药理学， AIM 3中的狗的遗传毒性和口服生物利用度。该项目的里程碑是选择优化的铅 临床前开发阶段发展的化合物，调查性新药物研究和 I期临床试验，用于诊断为MCRC的患者，一种致命的人类疾病。