After PROTAC, molecular glue dawns.

The use of small molecules to selectively regulate the function of proteins is the cornerstone of medical development.
, however, only about 20 percent of proteins in the human proteomics are thought to be regulated by this mechanism because they have functionally related lien pockets, such as active bits of enzymes.
from a drug development perspective, these proteins are defined as drug-forming proteins and are more likely to bind to small molecule drugs with high affinity.
how to target the remaining 80 percent of proteins in the proteomics, especially those known to be disease-related, is a major challenge in biomedical research.
now, scientists are using a protein degradation system that is naturally present in cells to overcome this problem.
drug-induced protein degradation is an emerging strategy to inactivate disease-related proteins that traditional inhibitors cannot cope with.
by mechanism of action, there are three kinds of degradation agent molecules: 1) price dioxide degradation agent represented by PROTACs;
PROTACs are relatively simple in design (connecting ubiganic connective enzyme ligands and specific target ligands with a linker), but these molecules tend to be larger and have adverse pharmaceutical properties.
, unit prices and molecular gel degradation agents are much smaller, making them very attractive.
in cells, E3 (Ubilin) connective enzymes can mark a small protein called ubibin as defective or damaged by attaching it to the target protein.
, the protein shredder (i.e., protease) in the cell processes the labeled target protein.
2004, three scientists from Israel and the United States won the Nobel Prize in Chemistry for their discovery of a "Ubigen-mediated process of protein degradation."
, the drug research and development of the hot - PROTACs technology is based on this mechanism, the first PROTACs drug has entered the clinical development stage.
the mechanism of action, these drugs are also known as protein degradation agents.
: In addition to PROTACs, scientists have found that a small molecule called a molecular glue (glue degrader) can also successfully induce the degradation of target proteins.
anti-cancer drugs such as
thalidamide are a significant example of molecular gel, which redirects the E3 ubiganic connective enzyme CRL4CRBN, thereby causing transcription factors IKZF1 and IKZF3 polysulphation, resulting in IKZF1 and IKZF3 degradation by proteases.
, the cancer-resistant sulfonamide drug indisulam guides CRL4DCAF15 E3 Ubiquitin connective enzyme degradation shear factors RBM23 and RBM39.
simple, molecular gel degradation agents are small molecules that induce a new type of interaction between the E3 Ubigan connecting enzyme substrate subject and the target protein, which leads to the degradation of the target protein.
, as with PROTACs, there is potential to significantly expand the pool of active-related pockets (pockets) on target proteins, as molecular glue reduces the need for pharmaceutically available protein targets.
molecular gel degradation agents are known to work by chemically redirecting cullin-RING ligases (CRLs).
CRLs are the largest family of E3 ubiganic connective enzymes, forming more than 250 CRLs by assembling substrate receptors (SRs) and adapter proteins around different cullin skeletons.
small molecule degradation agents usually work by redirecting CRL substrates such as CRBN or DCAF15.
, however, the discovery of new molecular glues is challenging, although existing molecular glues have shown the ability to target non-drug-resistant proteins such as transcription and shear factors.
, the existing molecular glue is accidentally discovered, there is no reasonable strategy to develop such drugs.
: In a new study published August 3 in the journal Nature Chemical Biology, a team of scientists from the Austrian Academy of Sciences reported on a new method they have developed to discover new molecular gel degradation agents through phenotypic chemical screening.
specifically, the researchers designed cellular systems with extensive damage to E3 connective enzyme activity and identified compounds that relied on active E3 connective enzymes by analyzing the differences in viability between these cell models and cells with normal E3 connective enzyme activity, which may be the new molecular gel degradation agent they were looking for.
Mayor-Ruiz and others compared the drug sensitivity of 2,000 drug compounds that inhibit cell growth and cytotoxicity in both cell linetes.
one of the cell line, CRLs activation is impaired by blocking the Ubibin modification of CRL, and in the other cell line, the Ubibin modification of CRL is normal.
drug resistance in the absence of ubibin modification suggests that the drug needs CRL to be active when it works in cells.
identified a new molecular gel degradation agent, dCeMM1 (Source: Nature Chemical Biology), which redirects CRL4DCAF15 connective enzymes, and researchers have integrated functional genomics, proteomics, and drug interaction strategies to identify the most promising compounds.
, they tested the feasible use of a new small molecule degradation agent by discovering a new RBM39 molecular gel degrader, dCeMM1.
dCeMM1 works by redirecting the activity of crL4DCAF15 connective enzymes, a structure very similar to other previously reported molecular glues.
dCeMM2/3/4 is a new class of structurally different cyclin K degradation agents (Source: Nature Chemical Biology) The researchers also found a new set of molecular glues that induce cyclin K degradation, dCeMM2/3/4.
cyclin K is essential in many different types of cancer.
CRISPR filtering, cyclin K degradation requires both CUL4 and DDB1.
dCeMM2/3/4 These new cyclin K degradation agents work through an unprecedented molecular mechanism involving "E3 CUL4B:DDB1": by facilitating the interaction between CDK12-cyclin K and CRL4B connective enzyme complex (Cullin 4B-Ring E3 ligase complex) to induce the generalization and degradation of Cyclink.
CUL4B belongs to the Cullin gene family and is the skeleton protein of the Cullin 4B-Ring E3 Ubigan connective enzyme complex (CRL4 connective enzyme complex), and DDB1 is the adapter protein of CULL4, which binds to more than 20 CRL4 substrates called DCAFs.
, DDB1-DCAF complexes recruit substrates to CRL4, but in this new study, scientists have found that CDK12-cyclin K can be combined directly with DDB1 (see figure below).
: Dr. George E. Winter, who led the study, believes the results provide the first framework for the discovery of molecular gel degradation agents.
, he said, "In the future, there is great hope that well-developed molecular gel degradation agents will be used to effectively remove pathogenic proteins that cannot be targeted through traditional pharmacological pathways."
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