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

基本信息

批准号：
10651880
负责人：
Anita Bellail
金额：
$ 97.95万
依托单位：
HB THERAPEUTICS, INC.
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：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10651880
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 Cytoplasm 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 Proliferating 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 Western Blotting Work Xenograft procedure absorption analog anti-cancer anticancer activity 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

项目摘要

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.

项目概要/摘要结直肠癌 (CRC) 是第四大确诊癌症，但也是第二大癌症死亡原因由于其肝脏和肺部的转移性疾病（mCRC），目前尚无有效的治疗方法。该项目的最终目标是开发小分子降解剂。泛素相关修饰物 1 (SUMO1) 作为用于治疗转移性结直肠癌的一流抗癌药物。为了实现这一目标，我们已经鉴定出一种能够选择性降解癌症中 SUMO1 蛋白的热门化合物但不是正常细胞，围绕命中化合物的结构-活性关系（SAR）研究已经产生了我们的结果。使用基因定义的 CRC 细胞系，具有改进的效力和类似药物特性的先导化合物，3- 三维（3D）类器官和患者来源的异种移植物（PDX），我们已经证明先导化合物比目前的标准疗法更有效地治疗转移性结直肠癌。建立一个具有足够能力的紧密联系的测试范式，包括所有必需的体外和体内测试体内测定已能够识别和表征当前 SBIR II 期先导系列。项目中，我们将优化我们的先导系列，旨在识别有效、选择性和口服生物可利用的 SUMO1 候选药物将具有必要的临床前功效、安全性和药代动力学。预测它能够全面探索 mCRC 患者的疗效和安全性，特别是目标 1。将利用我们的计算化学技术通过化学方法协助设计新型化合物先导系列的修饰将通过合理设计、合成和推进。首先，我们将使用我们的高容量初级筛选化合物。符合我们标准的化合物的结合和目标选择性的二次和反筛选测定。成功的将选择体外溶解度、渗透性、吸收、分布、代谢和排泄评估并优先考虑针对 CRC 细胞系和 3D 类器官的抗癌活性。从目标 1 研究中选出的主要化合物将在以下方面进行药代动力学特性评估：啮齿类动物将进一步评估所选化合物的体内清除率和口服生物利用度。口服给药后使用我们的 mCRC PDX 模型成功实现目标参与和治疗效果。化合物需要证明体内剂量反应目标与足够有效的结合转化为可接受的预测人类治疗剂量和治疗方案的最佳剂量。通过目标 2 中研究的化合物将进一步评估其毒理学、安全药理学、目标 3 中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先导药物用于进入临床前开发阶段、新药研究的化合物对诊断患有转移性结直肠癌（一种致命的人类疾病）的患者进行治疗的 I 期临床试验。