Targeting transcription factors by small compounds—Current strategies and future implications

Abstract

Transcription factors are central regulators of gene expression and critically steer development, differentiation and death. Except for ligand-activated nuclear receptors, direct modulation of transcription factor function by small molecules is still widely regarded as “impossible”.

This “un-druggability” of non-ligand transcription factors is due to the fact that the interacting surface between transcription factor and DNA is huge and subject to significant changes during DNA-binding. Besides some “success studies” with compounds that directly interfere with DNA binding, drug targeting approaches mostly address protein–protein interfaces with essential co-factors, transcription factor dimerization partners, chaperone proteins or proteins that regulate subcellular shuttling. An alternative strategy represent DNA-intercalating, alkylating or DNA-groove-binding compounds that either block transcription factor-binding or change the 3D-conformation of the consensus DNA-strand. Recently, much interest has been focused on chromatin reader proteins that steer the recruitment and activity of transcription factors to a gene transcription start site. Several small compounds demonstrate that these epigenetic reader proteins are exciting new drug targets for inhibiting lineage-specific transcription in cancer therapy.

In this research update we will discuss recent advances in targeting transcription factors with small compounds, the challenges that are related to the complex function and regulation of these proteins and also the possible future directions and applications of transcription factor drug targeting.

Introduction

For a long time the classical targets for improving cancer treatment have been receptors, kinases or other proteins involved in signal transduction, whereas transcription factors have long been considered as un-druggable targets. However, transcription factors are the central regulators of gene transcription and a large number of diseases, such as neurodegenerative disorders, diabetes and also cancer are associated with the deregulation of transcriptional networks. In fact it has been estimated that transcription factors account for 20% of oncogenes in cancer [1]. The understanding of these complex networks and pharmacological strategies to modulate the activity of distinct transcription factors will therefore be essential for the development of novel therapeutic approaches.

Most current strategies to modulate gene expression during e.g., cancer treatment indirectly affect transcription factors activity, since the inhibition of upstream kinases by specific small molecules results in modulation of multiple downstream pathways and therefore usually does not affect one single transcription factor. To further improve specific therapeutic intervention, minimize side effects and develop a “patient-specific therapy” the interest in directly targeting transcription factors has increased, since effective manipulation of these regulators may allow a “transcriptome-specific” therapy.

A proof for the relevance of directly modulating transcription factors in various therapies, most prominent cancer therapy, has been provided since many years/decades by targeting nuclear receptors that contain a clearly defined ligand-binding pocket and are activated by natural ligands, such as retinoic acid-, glucocorticoid-, estrogen-, or androgen-receptors. Activation or inhibition of these transcription factors is a central aspect of many standard cancer therapies as it leads to tumor cell type specific cell death and growth inhibition and the primary response to these therapeutics is of significant prognostic value. In fact e.g., the use of glucocorticoids in childhood leukemia represented a real therapeutic success story since its introduction 50 years ago. The use of these hormones/synthetic ligands is nowadays indispensable in cancer therapy as exemplified by the pronounced effects of glucocorticoids in leukemia, anti-estrogens in breast cancer or anti-androgens in prostate cancer therapy. However, almost all other transcription factors that lack pockets for activating ligands were ignored for drug discovery strategies and considered as “un-druggable”—a frequent comment from reviewers when grant proposals on this topic were rejected. One reason for neglecting these essential central regulators of life and death lies in the lack of a typical small binding pocket and the fact that usually the only clearly defined ligand is the cognate DNA-consensus sequence. In contrast to a steroid- or ATP-binding pocket this “ligand” requires a huge protein surface as interaction site on the transcription factor that is difficult to target with small compounds. Fortunately, our understanding of the transcription factor nucleosome complex has led to several “success stories” which have changed prevalent attitudes about targeting non-ligand transcription factors in drug discovery.