New Approach To Target “Undruggable” Proteins Identified

Molecular glue degraders may offer a solution for targeting proteins considered "undruggable", according to new research published in Nature Chemical Biology.

What makes a protein “undruggable”?

Undruggable proteins are a class of proteins that are difficult to target with traditional drugs, either due to them having a large or complex structure, or functions that are difficult to alter.

“Unlike proteins that can be targeted by conventional drugs, such as enzymes or receptors, “undruggable” proteins lack well-defined cavities, known as active sites, making the traditional inhibitory approach infeasible,” explained Dr. Zuzanna Kozicka, first author of the new research. “Such hard-to-reach targets represent approximately 80% of the human proteome and include, for example, transcription factors that often drive cancers.”

Recent advances in technology and drug design strategies are illustrating that fewer and fewer proteins are truly “undruggable”.

Molecular glue degraders bring the disposal machinery and the target protein together. “This drug-induced union results in the target protein being tagged for destruction with ubiquitin, ultimately leading to its degradation by the proteasome,” said Kozicka. “Such molecular matchmaking is an exciting and novel way to inactivate disease-causing proteins that were previously challenging to target.”

Targeting “posterchild” undruggable proteins

Kozicka highlights how thalidomide analogs – like REVLIMID® (lenalidomide) which is used to treat multiple myeloma – are successful drugs that were only identified as molecular glue degraders in retrospect.

“These compounds glue together a ubiquitin ligase complex (CRL4^CRBN) and several different proteins, among them posterchild undruggable targets, such as zinc finger transcription factors,” she explained.

An advantage of molecular glue degraders is that because they induce destruction of the target protein, they remove all protein functions, “including the more elusive ones such as scaffolding or modulating protein-protein or nucleic acid interactions,” said Kozicka.

She concluded: “Although designing molecular glue degraders remains a formidable challenge, new structural insights and an increasing number of examples bring us closer to understanding the underlying rules and unleashing their full potential in drug development.”   

Reference: Kozicka Z, Suchyta DJ, Focht V, et al. Design principles for cyclin K molecular glue degraders. Nat Chem Biol. 2024;20(1):93-102. doi: 10.1038/s41589-023-01409-z

Dr. Zuzanna Kozicka was speaking to Katie Brighton, Scientific Copywriter for Technology Networks.