Drugging the undruggable: transcription therapy for cancer

Abstract

Transcriptional regulation is often the convergence point of oncogenic signaling. It is not surprising, therefore, that aberrant gene expression is a hallmark of cancer. Transformed cells often develop a dependency on such a reprogramming highlighting the therapeutic potential of rectifying cancer-associated transcriptional abnormalities in malignant cells. Although transcription is traditionally considered as undruggable, agents have been developed that target various levels of transcriptional regulation including DNA binding by transcription factors, protein-protein interactions, and epigenetic alterations. Some of these agents have been approved for clinical use or entered clinical trials. While artificial transcription factors have been developed that can theoretically modulate expression of any given gene, the emergence of reliable reporter assays greatly facilitates the search for transcription-targeted agents. This review provides a comprehensive overview of these developments, and discusses various strategies applicable for developing transcription-targeted therapeutic agents.

Fig 1

Transcriptional regulation and targeting strategies. (A) Transcription is regulated at distinct levels. (B) Small molecules or polyamides compete with transcription factors to bind cis-regulatory elements, whereas decoys bind transcription factors preventing them from binding to promoters. (C) Peptide mimetics or small molecules disrupt dimerization of transcription factors, or interactions between transcription factors and their co-regulators. (D) Inhibition of DNA or histone modifying enzymes changes the epigenetic landscape with subsequent effects on gene expression. (E) Artificial transcription factors fused with transcriptional activation or repression domains bind to promoters, modulating transcriptional outcomes. TF, transcription factor; GTF, general transcription factor; Pol II, RNA polymerase II; CoR, transcription co-regulator; DNMT, DNA methyltransferase; HDAC, histone deacetylase; HMT, histone methyltransferase; I, transcription-targeted agents; D, transcription factor decoy; Me, methyl group; Ac, acetyl group; ZFP, zinc-finger protein; A/R, transcriptional activation or repression domain.

Fig 2

Chemical structures of transcription-targeted agents.

Fig 3

Reporter assays for high-throughput drug screening. (A) A bioluminescence reporter (Luc) driven by a cloned or synthetic promoter is randomly integrated into the genome for drug screening. (B) The recombinase Flp mediates homologous recombination between FRT (F) sites allowing site-specific integration of a reporter gene driven by a clone promoter into a pre-characterized open genomic location. (C) AAV mediated homologous recombination results in integration of a reporter gene into the native gene locus, allowing the reporter gene expression under control of the endogenous promoter and native chromatin environment. The selection gene is removed by Cre-mediated excision.