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 aberrant chimeric transcription factor ASPL-TFE3, in collaboration with Robert H. Shoemaker, Screening Technologies Branch, DTP, DCTD, 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 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.
|Zakharov, Alexey V; Peach, Megan L; Sitzmann, Markus et al. (2014) QSAR modeling of imbalanced high-throughput screening data in PubChem. J Chem Inf Model 54:705-12|
|Zakharov, Alexey V; Peach, Megan L; Sitzmann, Markus et al. (2014) A new approach to radial basis function approximation and its application to QSAR. J Chem Inf Model 54:713-9|