Transcription Factor Inhibition: Lessons Learned and Emerging Targets

Abstract

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.

Keywords: Myb; Myc; NF-κB; STAT; chemical probe; transcription factor.

Figure 1.. Inhibitors of the Stat family of transcription factors.

Upon stimulation, kinases such as JAKs phosphorylate Stat proteins, which can then dimerize via SH2 domains. Binding to importin allows translocation of phosphorylated Stat dimers into the nucleus, where they bind DNA and regulate transcription. Inhibitors of the Stat family of transcription factors have been found to affect various aspects of this pathway directly or indirectly.

Figure 2.. Modulators of NF-ĸB activity.

NF-ĸB is inactivated by association with IĸB proteins. Upon stimulation, IKK complexes phosphorylate IĸB proteins, leading to their degradation and allowing NF-ĸB to translocate to the nucleus and activate transcription. Inhibitors of NF-ĸB activity have been discovered to act directly or indirectly at various aspects of this pathway.

Figure 3.. Modulators of Myc-driven transcription.

A simplified diagram of Myc-driven transcription in which Myc/Max dimers generally activate transcription, while Max/Max homodimers attenuate Myc-driven transcription. While the majority of inhibitors of Myc-driven transcription disrupt the Myc/Max heterodimer, NSC13728 (which also has roles in affecting Myc/Max heterodimers) and KI-MS2–008 stabilize the Max homodimer to indirectly attenuate Myc activity.

Figure 4.

Significance of tissue specificity for targets nominated by the dependency map project. –log (P values) for P values computed between cancer cell lines of a specific type and all other cancer cell lines using empirical Bayes statistics. Data points were selected in October 2019 from specific types that were statistically different and more dependent than the rest of the cancer cell lines, using (A) CRISPR (Avana) data, (B) CRISPR (Sanger) data and (C) combined RNAi data from the Broad, Novartis, and Marcotte.