Monomeric Targeted Protein Degraders

Abstract

The discovery and development of targeted protein degraders have become important areas of research in the field of medicinal chemistry. Inducing degradation of a target protein presents several advantages relative to simple inhibition including a potential for extended duration of action and more profound pharmacology. While engineered heterodimeric molecules have recently been a major focus within industry and academia, this Perspective highlights examples of targeted protein degradation observed for smaller, monomeric molecules. Methods and tools for evaluating protein degradation as well as a discussion of physical properties of monomeric vs engineered heterodimeric degraders are presented.

Haven't got a glue: Protein surface variation for the design of molecular glue degraders

“…Following the elucidation of the mechanism of action of IMiDs and aryl sulfonamides, many other compounds, including prevalent ki-nase inhibitor drugs, have been suspected to have a degradation component to their mode of action. A clear molecular link between kinase inhibitors and the degradation machinery has remained elusive (Hanan et al, 2020;Jones, 2018). Recently, a bioinformatic screen for compounds whose cytotoxicity correlates with ligase mRNA levels across different cell lines pointed to CR8, a preclinical cyclin-dependent kinase (CDK) inhibitor, as a possible degrader (S1abicki et al, 2020a).…”

Multimodal small-molecule screening for human prion protein binders

“…Proofs of principle for this approach include the efficacy of monoclonal antibodies to PrP to clear prion infection in cell culture 12,13 and in peripheral tissues of animals 14 as well as the stability of PrP "stapled" with non-native disulfide bonds 15 . Alternatively, small-molecule binding events can sometimes directly lead to protein degradation 16,17 , and if not, a binder could serve as a starting point for engineering a bifunctional molecule to specifically target PrP for degradation 18,19 . Although at present most bifunctional degrader strategies are best suited to intracellular targets owing to reliance on cytoplasmic E3 ubiquitin ligases, recent studies suggest alternate routes to targeted degradation of cell surface proteins 20 such as PrP.…”

Emerging Trends in Cancer Drug Discovery—From Drugging the “Undruggable” to Overcoming Resistance

“…The opportunities are vast, but a major element of serendipity is needed to properly engage the targets that are of highest interest. The examples of fulvestrant and other selective estrogen receptor degraders, the BCL6 degrader BI-3802, and the selective BRD4 degrader GNE-0011 illustrate the exciting possibility of engendering target ligands with molecular features that can impart degradation (14)(15)(16). The degradation mechanisms utilized by such target ligand-based degraders are not known in all cases and could be diverse, distinguishing these compounds and this discovery approach from PROTACs and E3-ligase ligand-based glue molecules (13).…”