Discovery of molecular glue degraders

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The use of small molecules to selectively regulate the function of proteins is the cornerstone of the development of medicine. However, only about 20% of proteins in human proteomes are thought to be regulated by this mechanism because they have functional ligand pockets (such as enzyme active sites). From the drug development point of view, these proteins are defined as proprietary proteins and are more likely to bind to small molecule drugs with high affinity. How to target the remaining 80% of the proteome, especially those known to be disease-related, is a major challenge in biomedical research. Scientists are now using a naturally occurring protein degradation system in cells to overcome this problem.

Kinds of degraders Fig.1. Kinds of degraders

Drug-induced protein degradation is a new strategy to inactivate disease-related proteins that traditional inhibitors cannot deal with. Categorized by the mechanism of action, there are three kinds of degradants: bivalent degradants represented by Protacs, univalent degradants, and molecular glue degradants. In terms of design, Protacs is relatively simple, but these molecules tend to be large and have adverse drug properties. In contrast, univalent and molecular glue degradants can be much smaller and hence attractive.

Introduction of Protac®

In cells, E3 ubiquitin ligase can mark target protein as defective or damaged by attaching small proteins called ubiquitin. After that, the intracellular protein shredder will dispose the labeled target protein. In 2004, three scientists from Israel and the United States won the Nobel Prize in chemistry for discovering the “process of protein degradation mediated by ubiquitin”. At present, Protacs technology is popular in the field of drug research and development. The first Protacs drug has entered the clinical development stage. These drugs are also known as the protein degradants due to their mechanism of action.

Introduction of molecular glue

In addition to Protacs, a class of small molecules called molecular glue (glue degrader) can also successfully induce the degradation of target proteins. Thalidomide anticancer drugs are a prominent example of molecular glues. They can redirect E3 ubiquitin ligase CRL4CRBN to polyubiquitin transcription factors IKZF1 and IKZF3, resulting in proteasome degradation of IKZF1 and IKZF3. Similarly, the anticancer sulfonamides indisulam can induce CRL4DCAF15E3 ubiquitin ligase to degrade splicing factors RBM23 and RBM39.

Simply put, molecular gel degradants are small molecules that can induce a new interaction between E3 ubiquitin ligase substrate receptor and target protein, resulting in the degradation of target protein. Like Protacs, because molecular glue reduces the need for activity-related pockets on target proteins, it has the potential to greatly expand the protein target library of proprietary drugs.

Screening methods of molecular glue degradants

In a new study published in Nature Chemical Biology, a team of scientists from the Austrian Academy of Sciences reported a new method to identify new molecular glue degradants by phenotypic chemical screening[1].

Specifically, the researchers designed cell systems in which E3 ligase activity was widely impaired. They identified compounds dependent on active E3 ligase by analyzing the differences in viability between these cell models and cells with normal E3 ligase activity, and these compounds may be the new molecular glue degradants they are looking for.

Mayor-Ruiz[1] compared the drug sensitivity of 2000 anti-cell growth and cytotoxic compounds in two cell lines. In one cell line, the activation of CRL was impaired by blocking the ubiquitin modification of CRLs, while in the other cell line, the ubiquitin modification of CRL was normal. Drug resistance occurs in the absence of ubiquitin-like modification, indicating that CRL is active for drugs to work in cells.

The researchers integrated functional genomics, proteomics and drug interaction strategies to identify the most promising compounds. They first verified the feasibility of using this method to find new small molecular degradants by discovering a new RBM39 molecular gel degradant-dCeMM1. DCeMM1 works by redirecting the activity of CRL4DCAF15 ligase, and its structure is very similar to that of other molecular glues previously reported.

A new group of molecular glue-dCeMM2/3/4 that can induce the degradation of cyclin K was also discovered. Cyclin K is essential in many different types of cancer. CRISPR screening showed that both CUL4 and DDB1 were needed for cyclin K degradation. DCeMM2/3/4, a new cyclin K degrader, works through an unprecedented molecular mechanism involving “E3 CUL4B:DDB1.” It induces ubiquitination and degradation of CyclinK by promoting the interaction between CDK12-cyclin K and CRL4B ligase complex (Cullin 4B-Ring E3 ligase complex).

CUL4B belongs to the Cullin gene family and is the skeleton protein of Cullin4B-Ring E3 ubiquitin ligase complex (CRL4 ligase complex). DDB1 is the adapter protein of CUL4, which can bind to more than 20 CRL4 substrate receptors called DCAFs. Normally, DDB1-DCAF complexes recruit substrates to CRL4. But in this new study, scientists have found that CDK12-cyclin K can directly bind to DDB1.

DDB1-DCAF complexes recruit substrates to CRL4 Fig.2 DDB1-DCAF complexes recruit substrates to CRL4[1]

Dr. Georg E. Winter, who led the research, believes that the results provide the first framework for the discovery of molecular glue degradants. In the future, we have great hope to use well-developed molecular glue degradants to effectively remove disease-causing proteins that cannot be targeted through traditional pharmacological pathways.

Prospects and challenges

At present, it is known that molecular glue degradants work through chemical redirection of cullin-RING ligases (CRLs). CRLs is the largest family of E3 ubiquitin ligases, forming more than 250 kinds of CRLs by assembling substrate receptor (SRs) and adapter proteins around different cullin skeletons. Small molecular degradants usually work by redirecting CRL substrate receptors, such as CRBN or DCAF15.

However, although the existing molecular glues show the ability to target non-pharmaceutical proteins, such as transcription factors and splicing factors, the discovery of new molecular glues is very challenging. Since all the existing molecular adhesives were discovered by accident, there is no reasonable strategy for developing this kind of drugs at present.


  1. Mayor-Ruiz, C., Bauer, S., Brand, M., Kozicka, Z., Siklos, M., Imrichova, H., ... & Petzold, G. (2020). Rational discovery of molecular glue degraders via scalable chemical profiling. Nature Chemical Biology, 1-9.
  2. den Besten, W., & Lipford, J. R. (2020). Prospecting for molecular glues. Nature Chemical Biology, 1-2.