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

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.

项目总结/摘要 结直肠癌（CRC）是第四大诊断癌症，但主要是癌症死亡的第二大原因 由于其在肝脏和肺部的转移性疾病（mCRC）。目前尚无有效的治疗方法。 诊断为mCRC的患者。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（SUMO 1）作为治疗mCRC的首个抗癌药物。到 为了实现这一目标，我们已经确定了一种选择性降解癌症中SUMO 1蛋白的热门化合物 而不是正常细胞。围绕命中化合物的结构-活性关系（SAR）研究产生了我们的 具有改进的效力和药物样性质的先导化合物。使用基因定义的CRC细胞系，3- 三维（3D）类器官和患者来源的异种移植物（PDX），我们已经表明， 在治疗mCRC方面比目前的标准疗法更有效。我们早期的工作集中在 建立一个具有足够能力的良好连接的测试范例，包括所有需要的体外和 体内试验，能够识别和表征目前的铅系列。在SBIR第二阶段 项目，我们将优化我们的铅系列，目的是确定有效的，选择性的和口服生物可利用的SUMO 1 降级候选人。候选药物将具有必要的临床前疗效、安全性和药代动力学 预测它的性质使其能够在mCRC患者中充分探索有效性和安全性。具体而言，目标1 将利用我们的计算化学技术，通过化学方法来帮助设计新的化合物。 修改了Lead系列。每一种化合物都将被合理地设计、合成，并通过 我们建立的化合物测试漏斗首先，将使用我们的高容量初级筛选化合物， 用于其结合和靶选择性的二级和反筛选测定。符合我们标准的化合物 将根据体外溶解度、渗透性、吸收、分布、代谢和排泄选择成功的药物 评估并优先考虑针对CRC细胞系和3D类器官的抗癌活性。在目标2中， 从目标1的研究中选择的主要化合物将被评估其药代动力学性质， 啮齿动物，以确定清除率和口服生物利用度。将进一步评估所选化合物的体内 口服给药后使用我们的mCRC PDX模型的靶向结合和治疗功效。成功 化合物将需要证明体内剂量响应靶点接合， 剂量转换为可接受的预测人类治疗剂量和方案。优化的铅 通过目标2中的研究的化合物将进一步评价其毒理学，安全药理学， 目的3中犬的遗传毒性和口服生物利用度。这个项目的里程碑是选择优化的铅 用于推进到临床前开发阶段的化合物，调查性新药研究， I期临床试验，用于治疗诊断为mCRC（一种致命的人类疾病）的患者。