METHODS FOR SELECTING AND PRODUCING SELECTIVE PHARMACEUTICAL COMPOUNDS AND COMPOSITIONS USING AN ESTABLISHED GENETICALLY ALTERED CELL-BASED LIBRARY RESPONSIVE TO TRANSCRIPTION FACTORS; GENETIC CONSTRUCTS AND LIBRARY THEREFOR

摘要

The methods and products that are described in the present patent applicationare designed to determine by serial analysis the transcriptional activationpathways used by any compound of interest that is biologically active in acell. We have engineered a library of transgenic or recombinant cell linesthat allow the identification of simultaneous transcriptional pathwayspossibly used by the compound. Each cell line constituting the library hasbeen engineered by stable transfection thereof by retroviral integration, tocarry a reporter gene under the transcriptional control of a particulartranscription factor or family thereof endogenous to the host cell. This isachieved by having the expression of the reporter gene driven by a minimalpromoter and a transcription factor responsive-element (TF-RE) or a tandem orconcatemer thereof. In its complete form, the library contains a largecollection of reporter constructs responding to individual factors, each ofwhich can in turn be studied in a large repertory of cell lines. Such anapproach provides a global view of gene transcription activation in responseto diverse stimuli in multiple cellular environments and is a significantimprovement over case-by-case approaches. A compound screened against such alibrary provides a profile of selectivity for a given transcription factor andfor a given cell type, which profile is used to select good selective putativetherapeutics.