Focused Libraries for Epigenetic Drug Discovery: The Importance of Isosteres

Abstract

Epigenetic drug discovery provides a wealth of opportunities for the discovery of new therapeutics but has been hampered by low hit rates, frequent identification of false-positives, and poor synthetic tractability. A key reason for this is that few screening collections consider the unique requirements of epigenetic targets despite significant medicinal chemistry interest.Here we analyze the suitability of some commercially available screening collections in the context of epigenetic drug discovery, with a particular focus on lysine post-translational modifications, and show that even privileged motifs found in U.S. Food and Drug Administration (FDA)-approved drugs are not present in these collections. We propose that the incorporation of epigenetic bioisosteres should become central in the design of new focused screening collections and highlight some opportunities for the development of synthetic methods which may improve the tractability of hit molecules.

Advances in the Exploration of the Epigenetic Relevant Chemical Space

“…16 The principal component analysis was done based on six properties of pharmaceutical relevance: molecular weight, number of Recently, the need to include privileged substructures present in the collection of approved drugs for clinical use in the focused libraries for epigenetic drug discovery has been highlighted. 15 4.2. De Novo Design.…”

“…Recently, commercially available compound libraries focused on epigenetic targets have emerged. Table summarizes representative commercial libraries focused on epigenetic targets, including the number of compounds and the main targets.…”

“…Recently, the need to include privileged substructures present in the collection of approved drugs for clinical use in the focused libraries for epigenetic drug discovery has been highlighted …”

Chemoinformatic Characterization of Synthetic Screening Libraries Focused on Epigenetic Targets

“…Indeed, in epigenetic drug discovery, there are recent and increased efforts to design and analyze focused libraries. [5,6] By design, epigenetic-focused libraries have the potential to increase the epigenetic relevant chemical space, which has recently been revised. [7] Depending on the library developer, the compounds in the compound data sets are selected following a multi-step procedure, typically through computational approaches (although the specific methodological details remain undisclosed to the public).…”

“…In addition to the traditional general screening libraries available for high‐throughput screening, chemical companies have been assembling libraries focused on epigenetic targets [4] and the chemical structures are available in the public domain. Indeed, in epigenetic drug discovery, there are recent and increased efforts to design and analyze focused libraries [5,6] . By design, epigenetic‐focused libraries have the potential to increase the epigenetic relevant chemical space, which has recently been revised [7] …”