Pharmacological Modulation of Transcriptional Coregulators in Cancer

Abstract

Upon binding of transcription factors to cis-regulatory DNA sequences, transcriptional coregulators are required for the activation or suppression of chromatin-dependent transcriptional signaling. These coregulators are frequently implicated in oncogenesis via causal roles in dysregulated, malignant transcriptional control and represent one of the fastest-growing target classes in small-molecule drug discovery. However, challenges in targeting coregulators include identifying evidence of cancer-specific genetic dependency, matching the pharmacologically addressable protein fold to a functional role in disease pathology, and achieving the necessary selectivity to exploit a given genetic dependency. We discuss here how recent trends in cancer pharmacology have confronted these challenges, positioning coregulators as tractable targets in the development of new cancer therapies.

Keywords: cancer; chromatin; therapeutics; transcription.

Figure 1.. Mechanisms of transcriptional co-regulators.

Transcriptional co-regulators mediate transcription factor signaling via multiple molecular mechanisms. Chromatin remodelers alter nucleosome positioning and composition, chromatin writers add post-translational modifications (shown as orange circles) to histones and other proteins, histone erasers remove such post-translational modifications, and chromatin readers assemble regulatory complexes by anchoring onto histones with specific states of modification.

Figure 2, Key Figure.. Targeting transcriptional co-regulators in cancer.

(A) Recent examples of pharmacological agents able to disrupt transcriptional co-regulators. Small green circles indicate acetyl-lysine, small red circles indicate H3K27me3, and the small black circle on RNA Pol II represents post-translational phosphorylation.

Figure 3.. The emerging pharmacology of small-molecule protein degraders.

(A) Schematic showing the design of PROTACs. PROTACs are composed of a target protein ligand and an E3 ubiquitin ligase-binding ligand, connected by a linker region. PROTAC induce targeted protein degradation by simultaneously engaging a target protein and an E3 ubiquitin ligase complex, which results in poly-ubiquitination of the target protein and ultimately, proteasome-dependent degradation. (B) BET bromodomain inhibitors (blue ovals) inhibit the protein (BRD4) by occupying its druggable site and consequently disables its interaction with acetyl-lysine side chains (green circles) on chromatin. BRD4 PROTACs can act sub-stoichiometrically by directing multiple cycles of ubiquitination and degradation and remove the entire protein (BRD4) rather than inhibiting it.