Chemical Control of Genes: Synthetic Genome Readers and Gene Regulators.

Selective control of gene expression with small molecules has been a long-standing goal at the interface of chemistry and medicine. The ability to selectively regulate disease-driver genes with small molecules would transform the treatment of numerous human diseases. Small molecule modulators of proteins that enable gene transcription, including kinases, chromatin-modifying enzymes, and transcription factors (TFs) have proven invaluable as mechanistic probes and therapeutic agents. However, these molecules perturb gene regulatory processes broadly, often eliciting adverse outcomes and operating within narrow therapeutic ranges. Here, we describe the development of sequence-targeted synthetic gene regulators (SynGRs) that address these issues. Built with programmable DNA-binding polyamides, first-generation SynGRs were employed to inhibit gene expression by blocking the binding of TFs to regulatory sites. By contrast, gene-targeting chimeras that function as molecular glues to recruit the transcriptional machinery to targeted genes were developed to stimulate expression of desired gene(s). Since their advent in 2000, diverse classes of SynGRs have been reported, including artificial/synthetic TFs, protein-DNA dimerizers, and chromatin modifiers. Further integration of the principles of cooperative assembly and selectivity has yielded tunable SynGRs that regulate single disease-driver genes and are progressing as first-in-class therapeutic agents. The ability to rationally "drug" disease-driver genes is now within reach.