Transcription Factor Inhibition: Lessons Learned and Emerging Targets

Transcription factors have previously been nominated as targets in disease due to their location in focal points of signaling pathways. Significant progress has been made for many of these previously suggested transcription factors, including the STAT family, NF-κB, and Myc, resulting in small molecules inhibiting transcription factor activity in cell culture, and in some cases, in vivo. The cancer dependency map project uncovered many critical proteins in human cancers based on genome-wide loss-of-function screens, and transcription factors represent a large class of the dependencies. Among these, a number of transcription factors, including Myb, have limited or no suitable small molecule probes, and chemical probe research on these transcription factors will be a major area of interest moving forward.Transcription factors have roles at focal points in signaling pathways, controlling many normal cellular processes, such as cell growth and proliferation, metabolism, apoptosis, immune responses, and differentiation. Their activity is frequently deregulated in disease and targeting this class of proteins is a major focus of interest. However, the structural disorder and lack of binding pockets have made design of small molecules for transcription factors challenging. Here, we review some of the most recent developments for small molecule inhibitors of transcription factors emphasized in James Darnell’s vision 17 years ago. We also discuss the progress so far on transcription factors recently nominated by genome-scale loss-of-function screens from the cancer dependency map project.National Cancer Institute (Grant R01-CA160860