In Silico Screening for Cancer Targets

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

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.