In Silico Screening for Cancer Targets

与CCR/NCI的几位主要研究者合作，正在对大型小分子数据库进行计算机筛选，以获得许多与癌症相关的分子靶点。我们正在使用CADD集团的资源，包括我们的筛选数据库，以生成从商业供应商购买的化合物列表，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。目前，我们主要致力于靶点Akt（PH结构域），与Chris霍兰德（癌症治疗分支，CCR，NCI）合作; c-Met，与Donald Bottaro（泌尿肿瘤分支，CCR，NCI和Terrence R）合作。小伯克，化学生物学实验室（CBL），CCR，NCI; polo样激酶1的polo-Box结构域，与Kyung S. Lee，代谢实验室，CCR，NCI; Grb 2 SH 2结构域，与Terrence R.小伯克，PKC，与Peter Blumberg合作，癌症生物学和遗传学实验室，CCR，NCI，维克托E. Marquez（Emeritus），CBL，CCR，NCI，and Julieta Comin，Instituto Nacional de Tecnologia Industrial，Argentina;疱疹胸苷激酶，与维克托E. Marquez，药物化学实验室，CCR，NCI;双咪唑并吖啶酮DNA嵌入剂，与Sergey Tarasov，结构生物物理实验室，CCR，NCI合作;血小板反应蛋白-1（TSP 1）与CD 47相互作用的表面补丁的小分子模拟物，以及与大卫D. Roberts，病理学实验室，CCR，NCI;转录因子HIF-1 α与辅因子p300的相互作用，与William道格拉斯Figg Sr.合作，医学肿瘤学分支，CCR，NCI;通过靶向CBF-β和Runx 1相互作用开发CBF白血病的靶向治疗，与Paul Liu，NHGRI，NIH合作; CADD工作，与Christoph Rader，抗体技术科，ETIB，CCR，NCI合作开发HIV-1 Rev抑制剂;与John S.小施尼克洛斯，CBL、CCR、NCI;与Jordan Meier、CBL、CCR、NCI合作，为赖氨酸乙酰转移酶抑制剂的筛选提供建模支持;与Kevin Gardner、CCR、NCI转录调控部遗传学分支合作，为C-末端结合蛋白的抑制剂进行建模和计算机模拟筛选;与Terry W.穆迪OD CCR NCI对于Akt、c-Met、plk 1的polo-Box结构域、Tdp 1和TSP 1/CD 47，已生成初始命中集，购买筛选样品，并由我们的合作者分析这些样品。在这些试验的每一个中，在许多样品中发现了抑制活性。在CD 47/SIRPa项目中，我们已经完成了对CD 47和SIRPa之间相互作用的抑制剂的另一个筛选。已购买样品并进行了分析，确定了具有有趣生物活性的命中物，并提交了EIR。这些努力已经导致了几项专利申请和/或与CADD集团成员共同发明人授予的专利。最近在这一领域的一项新合作是与Jeff Gildersleeve博士，CBL，CCR，NCI，关于神经节苷脂GD 2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.