In Silico Screening for Cancer Targets

癌症靶标的计算机筛查

• 批准号: 10703019
• 负责人: MARC NICKLAUS
• 金额: $ 18.06万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703019
• 关键词: 2019-nCoV; Academic Medical Centers; Acetyltransferase; Area; Argentina; Bacterial Counts; Biological Assay; C-terminal binding protein; CBL gene; CCR; CD47 gene; COVID-19 pandemic; Cell Death; Cells; Chronic; Clinical; Collaborations; Computer software; Core-Binding Factor; DNA; Databases; Development; Dimerization; EP300 gene; Epithelial Cells; Evolution; Ganglioside GD2; Genes; Goals; HIF1A gene; HIV-1; Immune; Immune response; Immunologics; In Vitro; Industrialization; Intercalating Agents; International; Jordan; Laboratories; Legal patent; Lysine; Malignant Neoplasms; Methods; Modeling; Molecular Target; Mus; Mycobacterium tuberculosis; N-terminal; National Human Genome Research Institute; New York; Pathology; Pharmaceutical Chemistry; Principal Investigator; Property; Proteins; RAS genes; Resources; STAT3 gene; Screening for cancer; Shipping; Signal Transduction; Structure; Sumoylation Pathway; Surface; Testing; Thalidomide; Therapeutic antibodies; Thrombospondin 1; Thymidine Kinase; Time; United States National Institutes of Health; Work; analog; base; cofactor; design; dimer; helicase; in silico; inhibitor; interest; leukemia; mimetics; neoplastic cell; novel; novel lead compound; novel therapeutics; programs; screening; small molecule; small molecule inhibitor; success; targeted treatment; transcription factor

In collaboration with several Principal Investigators at the CCR/NCI, in silico screening of large small-molecule databases are being conducted for a number of molecular targets relevant for cancer. We are using the CADD Group's resources, including our screening databases to generate lists of compounds to be purchased from commercial suppliers, with the goal of obtaining novel lead compounds in in vitro and/or cell-based assays. We have been working with Julieta Comin, Instituto Nacional de Tecnologia Industrial, Argentina; herpes thymidine kinase, in collaboration with Victor E. Marquez, formerly Laboratory of Medicinal Chemistry, CCR, NCI; bis-imidazoacridone DNA intercalators, in collaboration with Sergey Tarasov, CSB, CCR, NCI; small-molecule mimetics of a surface patch of thrombospondin-1 (TSP1) interacting with CD47 as well as for the interacting SIRP-alpha protein, in collaboration with David D. Roberts, Laboratory of Pathology, CCR, NCI; the interaction of the transcription factor HIF-1 alpha with cofactor p300, in collaboration with William Douglas Figg Sr., GMB, CCR, NCI; the development of targeted therapy for CBF leukemias by targeting the CBF-beta and Runx1 interaction, in collaboration with Paul Liu, NHGRI, NIH; in silico screening and modeling support for screening for SUMOylation inhibitors, in collaboration with John S. Schneekloth, Jr., CBL, CCR, NCI; modeling support for screening for lysine acetyltransferase inhibitors, in collaboration with Jordan Meier, CBL, CCR, NCI; modeling and in silico screening for inhibitors of C-Terminal Binding protein, in collaboration with Kevin Gardner, Columbia University Medical Center, New York, NY. A collaboration in this area is with Jeff Gildersleeve, CBL, CCR, NCI, on the Immunological Evolution of Therapeutic Antibodies to Ganglioside GD2. A collaboration is with Jay Schneekloth about HRAS. Recent in silico screening collaborations are with Euna Yoo on USP18, Martin Schnermann on PBD dimers, Andre Nussenzweig on Werner helicase, Stan Lipkowitz on Cbl-b, Doug Figg/Dong Seok Kim (AevisBio) on thalidomide analogs, Kevin Gardner on CtBP, and Javed Khan & Bob Hawley on KDM3B. A very important part of our in silico screening collaboration is with Nadya Tarasova, CIL, CCR, NCI, in the context of our SAVI project, by applying the SAVI Database to find active molecules against cancer, SARS-Cov-2 targets, and, to some extent, HIV-1, targets. A recent success story involves our work on STAT3 N-terminal domain (ND), is a promising target since it has been shown that a STAT3 ND lipopeptide inhibitor induces cell death through activation of proapoptotic genes in tumor cells but not normal epithelial cells. Such inhibitors also showed immune stimulatory properties and caused significant reduction in bacterial count in mice chronically infected with Mycobacterium tuberculosis by activating host immune responses. The STAT3 ND structure was tested experimentally to find a druggable pocket. Out of four analyzed, one pocket next to its dimerization interface was found by Dr. Tarasova's group to yield small molecule leads in the screening that are more potent than lipopeptide STAT3 ND inhibitors. The compounds suppress STAT3 signaling and are selectively toxic to tumor cells. An International Patent Application (No. PCT/US2021/058936) for these compounds was filed November 11, 2021 with the title SMALL MOLECULE INHIBITORS OF STAT3 N-TERMINAL DOMAIN AND METHODS OF USE. The time from initial in silico screening to patent application was just 15 months, which included all the slowdowns caused by the COVID-19 pandemic such as shutdown of wet labs for months and delays in synthesis and shipping of compounds from Enamine. Additional recent enhancement to the screening workflow involves the use of MolSoft's program RIDE that allows to efficiently screen the entire database to select the most promising leads.

与 CCR/NCI 的几位首席研究员合作，正在对大型小分子数据库进行计算机筛选，以找出许多与癌症相关的分子靶标。我们正在利用 CADD 集团的资源，包括我们的筛选数据库来生成从商业供应商处购买的化合物列表，目的是在体外和/或基于细胞的测定中获得新型先导化合物。我们一直与阿根廷国家工业技术研究所的 Julieta Comin 合作；疱疹胸苷激酶，与 Victor E. Marquez（前 CCR、NCI 药物化学实验室）合作；双咪唑吖啶酮 DNA 嵌入剂，与 Sergey Tarasov、CSB、CCR、NCI 合作；与 CD47 相互作用的血小板反应蛋白-1 (TSP1) 表面斑块以及相互作用的 SIRP-α 蛋白的小分子模拟物，与 CCR、NCI 病理学实验室的 David D. Roberts 合作；与 William Douglas Figg Sr.、GMB、CCR、NCI 合作，研究转录因子 HIF-1 α 与辅因子 p300 的相互作用；与 Paul Liu、NHGRI、NIH 合作，通过针对 CBF-beta 和 Runx1 相互作用开发 CBF 白血病靶向治疗；与 John S. Schneekloth, Jr.、CBL、CCR、NCI 合作，为 SUMOylation 抑制剂的筛选提供计算机模拟筛选和建模支持；与 Jordan Meier、CBL、CCR、NCI 合作，为筛选赖氨酸乙酰转移酶抑制剂提供建模支持；与纽约哥伦比亚大学医学中心的 Kevin Gardner 合作，对 C 端结合蛋白抑制剂进行建模和计算机筛选。该领域与 Jeff Gildersleeve（CBL、CCR、NCI）合作，研究神经节苷脂 GD2 治疗性抗体的免疫学进化。与 Jay Schneekloth 就 HRAS 进行合作。最近的计算机筛选合作包括与 Euna Yoo 进行 USP18、Martin Schnermann 进行 PBD 二聚体、Andre Nussenzweig 进行 Werner 解旋酶、Stan Lipkowitz 进行 Cbl-b、Doug Figg/Dong Seok Kim (AevisBio) 进行沙利度胺类似物、Kevin Gardner 进行 CtBP 以及Javed Khan 和 Bob Hawley 在 KDM3B 上。我们的计算机筛选合作的一个非常重要的部分是与 Nadya Tarasova、CIL、CCR、NCI 在我们的 SAVI 项目背景下，通过应用 SAVI 数据库来寻找抗癌活性分子、SARS-Cov-2 靶标，以及，在某种程度上，HIV-1是目标。最近的一个成功案例涉及我们对 STAT3 N 末端结构域 (ND) 的研究，它是一个有前途的靶点，因为已表明 STAT3 ND 脂肽抑制剂通过激活肿瘤细胞中的促凋亡基因（而非正常上皮细胞）来诱导细胞死亡。此类抑制剂还表现出免疫刺激特性，并通过激活宿主免疫反应，导致慢性感染结核分枝杆菌的小鼠的细菌数量显着减少。通过实验测试 STAT3 ND 结构以找到可药物口袋。 Tarasova 博士的研究小组发现，在分析的 4 个样本中，其二聚化界面旁边的一个口袋可在筛选中产生比脂肽 STAT3 ND 抑制剂更有效的小分子先导物。这些化合物抑制 STAT3 信号传导并对肿瘤细胞具有选择性毒性。这些化合物的国际专利申请（No. PCT/US2021/058936）于2021年11月11日提交，标题为STAT3 N-末端结构域的小分子抑制剂和使用方法。从最初的计算机筛选到专利申请的时间仅为 15 个月，其中包括 COVID-19 大流行造成的所有放缓，例如实验室关闭数月以及 Enamine 化合物的合成和运输延迟。最近对筛选工作流程的其他增强包括使用 MolSoft 的 RIDE 程序，该程序可以有效地筛选整个数据库以选择最有希望的线索。