Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

Abstract

Cancer is associated with epigenetic changes such as abnormal DNA methylation and histone tail modifications, and these changes result in tumor suppressor gene silencing, oncogene overexpression, and genome instability -phenomena that are closely linked to cancer development. The epigenetic marks on DNA and histones are reversible and therefore it is possible to restore normal patterns through chemically targeting epigenetic regulators that generate, maintain, recognize, and remove these marks. In recent years, fragment-based drug discovery (FBDD) has been used to target both the protein-protein interactions (PPI) as well as the enzymatic functions of epigenetic factors. Low molecular weight fragments (MW<300) efficiently sample chemical space and can bind to discreet binding pockets on target proteins such as those found on PPI interface. In this review, we describe the biophysical, biochemical, and in silico methods used for FBDD. We also discuss the examples of using FBDD to target epigenetic readers such as bromodomain-containing proteins and epigenetic enzymes such as arginine methyltransferases 6 (PRMT6), lysine demethylase 4 (KDM4), and Sirtuin 2 (SIRT2). FBDD provides an economical alternative to traditional high throughput screening. Effective FBDD endeavors depend heavily on gaining structural information of ligand-protein interactions early on and the close collaboration between biophysicists, chemists, and biologists in all stages of the drug discovery process. Using FBDD, protein-protein interactions in non-enzymatic epigenetic factors can potentially be chemically modulated. Furthermore, FBDD enables the identification of new binding pockets that can improve compound specificity against various epigenetic enzymes.

Using NMR Spectroscopy in the Fragment‐Based Drug Discovery of Small‐Molecule Anticancer Targeted Therapies

“…The adequacy of NMR screening in FBDD is highlighted by its sensitivity; while small‐molecule fragments will often yield no signal in most binding assays due to weak interactions, such binding can be reliably detected using NMR spectroscopy [34,94] . Therefore, the technique allows promising fragments that might otherwise go unnoticed to be spotted.…”

“…The adequacy of NMR screening in FBDD is highlighted by its sensitivity; while small-molecule fragments will often yield no signal in most binding assays due to weak interactions, such binding can be reliably detected using NMR spectroscopy. [34,94] Therefore, the technique allows promising fragments that might otherwise go unnoticed to be spotted. This makes NMR-based FBDD well-suited towards the challenge posed by "undruggable targets", as it is favorably placed to facilitate the discovery of leads against these seemingly intractable structures, including PPIs, shallow binding pockets, or vast hydrophobic surfaces.…”