In Silico Screening for Cancer Targets

与CCR/NCI的几位首席研究员合作，正在对与癌症相关的一些分子靶点进行大型小分子数据库的计算机筛选。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清单，目的是在体外和/或细胞基础试验中获得新的先导化合物。目前，我们主要致力于靶标Akt （PH结构域），与Chris Hollander合作，癌症治疗分支，CCR， NCI；c-Met与NCI CCR泌尿肿瘤科的Donald Bottaro和NCI CCR化学生物学实验室（CBL）的Terrence R. Burke合作；polo样激酶1的polo-Box结构域，与Kyung S. Lee合作，代谢实验室，CCR， NCI；Grb2 SH2域，与Terrence R. Burke, Jr.合作，CBL， CCR， NCI；PKC与Peter Blumberg，癌症生物学和遗传学实验室，CCR， NCI, Victor E. Marquez（荣誉退休），CBL， CCR， NCI，和Julieta Comin，阿根廷国家工业技术研究所合作；疱疹胸苷激酶，与Victor E. Marquez合作，药物化学实验室，CCR， NCI；双咪唑吖啶酮DNA插入物，与Sergey Tarasov合作，结构生物物理实验室，CCR， NCI；与NCI CCR病理学实验室David D. Roberts合作，研究了血小板反应蛋白-1 （TSP1）表面斑块与CD47相互作用以及与sirp - α蛋白相互作用的小分子模拟物；转录因子HIF-1 α与辅因子p300的相互作用，与NCI CCR内科肿瘤学分会William Douglas Figg Sr合作；与NIH NHGRI的Paul Liu合作，通过靶向CBF- β和Runx1相互作用开发针对CBF白血病的靶向治疗；CADD致力于HIV-1 Rev抑制剂的开发，与抗体技术部，ETIB， CCR， NCI的Christoph Rader合作；与John S. Schneekloth, Jr.， CBL， CCR， NCI合作，进行SUMOylation抑制剂的筛选和建模支持；赖氨酸乙酰转移酶抑制剂筛选的建模支持，与Jordan Meier， CBL， CCR， NCI合作；c端结合蛋白抑制剂的建模和计算机筛选，与NCI CCR转录调控部遗传学分部的Kevin Gardner合作；与Terry W. Moody （OD， CCR， NCI）合作，研究肺癌bombesin受体配体的建模和抑制剂开发。对于Akt， c-Met, plk1， Tdp1和TSP1/CD47的polo-Box结构域，我们已经生成了初始命中集，筛选了购买的样本，并由我们的合作者对这些样本进行了分析。抑制活性被发现为许多样品在这些分析中的每一个。在CD47/SIRPa项目中，我们完成了CD47和SIRPa相互作用抑制剂的另一个筛选。已购买并分析了样品，确定了具有有趣生物活性的命中点，并存档了EIR。这些努力已经产生了一些专利申请和/或与CADD小组成员共同发明人授予的专利。最近在这一领域的新合作是与Jeff Gildersleeve博士，CBL， CCR， NCI，关于神经节苷脂GD2治疗性抗体的免疫学进化。

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. Currently, we are predominantly working on the targets Akt (PH domain), in collaboration with Chris Hollander, Cancer Therapeutics Branch, CCR, NCI; c-Met, in collaboration with Donald Bottaro, Urologic Oncology Branch, CCR, NCI, and Terrence R. Burke, Jr., Chemical Biology Laboratory (CBL), CCR, NCI; polo-Box domain of polo-like kinase 1, in collaboration with Kyung S. Lee, Laboratory of Metabolism, CCR, NCI; Grb2 SH2 domain, in collaboration with Terrence R. Burke, Jr., CBL, CCR, NCI; PKC, in collaboration with Peter Blumberg, Laboratory of Cancer Biology and Genetics, CCR, NCI, Victor E. Marquez (Emeritus), CBL, CCR, NCI, and Julieta Comin, Instituto Nacional de Tecnologia Industrial, Argentina; herpes thymidine kinase, in collaboration with Victor E. Marquez, Laboratory of Medicinal Chemistry, CCR, NCI; bis-imidazoacridone DNA intercalators, in collaboration with Sergey Tarasov, Structural Biophysics Laboratory, 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., Medical Oncology Branch, 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; CADD work for the development of HIV-1 Rev inhibitors, in collaboration with Christoph Rader, Antibody Technology Section, ETIB, CCR, NCI; 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, Genetics Branch, Transcription Regulation Section, CCR, NCI; and modeling and inhibitor development of bombesin receptor ligands for lung cancer, in collaboration with Terry W. Moody, OD, CCR, NCI. For Akt, c-Met, the polo-Box domain of plk1, Tdp1, and TSP1/CD47, initial hit sets have been generated, screening samples purchased, and these samples assayed by our collaborators. Inhibitory activity was found for a number of samples in each one of these assay. In the CD47/SIRPa project we have completed another screen for inhibitors of the interaction between CD47 and SIRPa. Samples have been purchased and assayed, hits with interesting biological activity identified, and an EIR filed. These efforts have resulted in several patent applications and/or patents granted with CADD Group members a co-inventors. A recent new collaboration in this area is with Dr. Jeff Gildersleeve, CBL, CCR, NCI, on the Immunological Evolution of Therapeutic Antibodies to Ganglioside GD2.