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Development of an oral drug targeting SUMOylation

开发针对 SUMOylation 的口服药物

基本信息

批准号：
9407583
负责人：
Victor Cee
金额：
$ 23.28万
依托单位：
SUVALENT THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-18 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9407583
关键词：
Address Animal Model Biological Availability CD47 gene Cancer Patient Cell Line Cell model Cells Cellular Assay Characteristics Colorectal Cancer Development Drug Industry Drug Kinetics Drug Targeting Enzyme Inhibitor Drugs Enzymes FDA approved Formulation Funding Future Gene Expression Profiling Genes Goals Immune response In Vitro Knowledge Lead Letters Literature MYC gene Malignant Neoplasms Medical Modification Molecular Abnormality Mus Oncogenes Oral PDCD1LG1 gene Pathway interactions Patients Pharmaceutical Preparations Phase Post-Translational Protein Processing Property Protein Family Proteins Resources Safety Scheme Scientific Advances and Accomplishments Small Business Innovation Research Grant Specificity Testing Therapeutic Therapeutic Agents Therapeutic Studies Tissues Toxic effect Toxicology Translating Tumor Immunity Ubiquitin anti-tumor immune response anticancer research base c-myc Genes cancer cell cancer survival cancer therapy cancer type chemical synthesis clinical development colon cancer cell line colorectal cancer treatment commercialization drug metabolism genome-wide high throughput screening improved in vivo inhibitor/antagonist innovation insight interest lead optimization new therapeutic target novel overexpression phase 2 study programs scale up small molecule inhibitor stemness targeted treatment

项目摘要

c-Myc- and KRas-dependent cancers, such as colorectal cancer, represent major unmet medical needs that currently lack targeted therapy. Recent scientific advances revealed that these “undruggable” oncogenes critically depend on post-translational modification with the small ubiquitin-like modifier (SUMO) family of proteins, and inhibiting SUMOylation inhibits c-Myc and KRas. Furthermore, SUMOylation inhibition can activate anti-tumor immune responses. Genome- wide gene expression analysis has demonstrated that the SUMO activating enzyme (E1) is the most overexpressed SUMOylation-related protein in colorectal cancers tissues. SUMO E1 overexpression is also associated with cancer cell stemness and poor patient survival. This evidence makes SUMO E1 an attractive target. Therefore, we propose to develop highly selective, potent, and orally available SUMO E1 inhibitors as targeted therapies for colorectal cancer. Using a high-throughput screening campaign, we have identified a class of potent and specific SUMO E1 inhibitors suitable for development into orally available drugs, which could represent a new class of therapeutic agents. We will conduct lead optimization of these compounds and validate the resulting candidates in cellular assays of colorectal cancer, followed by pharmacokinetic and toxicity studies. In addition to colorectal cancer, which is the focus of our proposal, inhibiting SUMOylation will likely inhibit other c-Myc and KRas-dependent cancers. Thus, the potent SUMO E1 inhibitors developed in the proposed studies are expected to have a major impact on cancer research and targeted therapy.

c-Myc和KRas依赖性癌症，如结直肠癌，代表了主要的未满足的医疗需求。目前缺乏有针对性的治疗。最新的科学进展表明， “不可治疗的”癌基因严重依赖于翻译后修饰，泛素样修饰蛋白（SUMO）家族，抑制SUMO化可抑制c-Myc和克拉斯此外，SUMO化抑制可以激活抗肿瘤免疫应答。基因组- 广泛的基因表达分析表明，SUMO激活酶（E1）是在结直肠癌组织中最高表达的SUMO化相关蛋白。相扑E1 过表达还与癌细胞的干细胞性和患者存活率低有关。这有证据表明相扑E1是一个有吸引力的目标。因此，我们建议开发高选择性，有效的口服SUMO E1抑制剂作为结直肠癌的靶向治疗。使用高通量筛选活动，我们已经确定了一类有效的和特定的SUMO E1 适合开发成口服药物的抑制剂，这可能代表一类新的药物治疗剂。我们将对这些化合物进行先导优化，并验证在结肠直肠癌的细胞测定中产生候选物，然后进行药代动力学和毒性研究。除了大肠癌，这是我们建议的重点，抑制 SUMO化可能会抑制其他c-Myc和KRas依赖性癌症。而强大的，在拟议的研究中开发的E1抑制剂预计将对癌症产生重大影响研究和靶向治疗。