Related Experiment Video
Updated: Feb 4, 2026
Rapid Synthesis and Screening of Chemically Activated Transcription Factors with GFP-based Reporters
Published on: November 26, 2013
GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor
Shumei Wang1, Vickie Tsui1, Terry D Crawford1
1Genentech Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
Abstract:
The biological functions of the dual bromodomains of human transcription-initiation-factor TFIID subunit 1 (TAF1(1,2)) remain unknown, although TAF1 has been identified as a potential target for oncology research. Here, we describe the discovery of a potent and selective in vitro tool compound for TAF1(2), starting from a previously reported lead. A cocrystal structure of lead compound 2 bound to TAF1(2) enabled structure-based design and structure-activity-relationship studies that ultimately led to our in vitro tool compound, 27 (GNE-371). Compound 27 binds TAF1(2) with an IC50 of 10 nM while maintaining excellent selectivity over other bromodomain-family members. Compound 27 is also active in a cellular-TAF1(2) target-engagement assay (IC50 = 38 nM) and exhibits antiproliferative synergy with the BET inhibitor JQ1, suggesting engagement of endogenous TAF1 by 27 and further supporting the use of 27 in mechanistic and target-validation studies.
Insights
Researchers developed a selective compound, GNE-371, targeting TAF1(2) bromodomains for oncology research. This tool compound shows potent activity and selectivity, aiding in TAF1 target validation studies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The biological roles of the dual bromodomains in human transcription-initiation-factor TFIID subunit 1 (TAF1(1,2)) are not fully understood.
- TAF1 is recognized as a potential therapeutic target in cancer research.
Purpose of the Study:
- To discover and characterize a potent and selective chemical probe for the TAF1(2) bromodomain.
- To validate TAF1 as a target for potential oncology applications.
Main Methods:
- Structure-based drug design utilizing cocrystal structures of TAF1(2) and lead compounds.
- Structure-activity relationship (SAR) studies to optimize compound potency and selectivity.
- In vitro biochemical assays (IC50 determination) and cellular target engagement assays.
Main Results:
- Identification of compound 27 (GNE-371) as a potent and selective inhibitor of TAF1(2) with an IC50 of 10 nM.
- Compound 27 demonstrated excellent selectivity against other bromodomain family members.
- GNE-371 showed cellular activity (IC50 = 38 nM) and antiproliferative synergy with BET inhibitor JQ1, indicating engagement of endogenous TAF1.
Conclusions:
- Compound 27 (GNE-371) serves as a valuable in vitro tool for mechanistic studies and target validation of TAF1.
- The findings support TAF1 as a promising target for further investigation in oncology drug discovery.
Related Concept Videos
02:16Transcription Factors
02:35Transcription Elongation Factors
The transcription elongation is regulated via pausing of RNA polymerase on several occasions during transcription. In bacteria, these halts are necessary because the transcription of DNA into mRNA is coupled to the translation of that mRNA...
02:35Transcription Elongation Factors
01:47Transcription Initiation
The promoters and enhancers and their accessory proteins allow tight regulation of...
02:33Initiation of Translation
First, the initiator tRNA must be selected from the pool of elongator tRNAs by eukaryotic initiation factor 2 (eIF2). The initiator tRNA (Met-tRNAi) has conserved sequence elements including modified bases at...
01:30General Transcription Factors