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The above-mentioned molecules reflect the richness of the structure and application types of degradants, but there is still a long way to go for the rational design and continuous optimization of degradant molecules and activity detection
PROTAC mainly relies on the ubiquitin-proteasome pathway, and its corresponding degradation is mostly cytoplasmic and nuclear proteins
In the PROTAC-mediated protein degradation pathway, the efficient formation of ternary complexes such as target ligand (POI)-PROTAC-E3 ligase also plays an important role
In addition, in activity studies, the term cooperativity (α) was used to explain that PROTACs are affected by protein-protein interactions (PPIs) between POIs and E3 ligase ligands
Figure 1.
PROTAC mainly relies on the ubiquitin-proteasome pathway, and its corresponding degradation is mostly cytoplasmic and nuclear proteins
Figure 2.
They build on a previous finding by Clausen's lab that in Bacillus subtilis and other Gram-positive bacteria, the ClpC–ClpP (ClpCP) protease, composed of the AAA unfoldase ClpC and the protease ClpP, is a protease that degrades unfolded and aggregated proteins in bacteria important proteolytic enzymes
The bacterial PROTACs (BacPROTACs) reported by Morreale et al.
Figure 3.
Due to the problems of chemical stability of phosphoarginine, its application in vivo is limited
Figure 4.
Degradability evaluation
Summarize
PROTAC has derived a class of molecules in the mode of "POI ligand-Linker-degradation system guide", which complements the deficiency of PROTAC as a degradation agent in the degradation of certain protein and non-protein molecules, and endows the degradation agent with this role.
Concept more possibilities
.
In addition to the difference between the activity test results and conventional molecules caused by the molecule's own mechanism of action, the appropriate degradation pathway has a particularly great influence on the activity
.
MCE is the world's leading supplier of scientific research chemicals and bioactive compounds.
It can provide scientists with PROTAC related products.
At present, we have various products such as PROTAC, AUTAC, ATTEC, molecular glue and their building blocks online
.
At the same time, we also provide integrated synthesis services for PROTAC products
.
All MCE products are used for scientific research or drug certification only, we do not provide products and services for any personal use
.
1.
Jin J, Wu Y, Chen J, Shen Y, Zhang L, Zhang H, Chen L, Yuan H, Chen H, Zhang W, Luan X.
The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination.
Theranostics.
2020 Aug 8;10(22):10141-10153.
Grohmann, C.
, Magtoto, CM, Walker, JR et al.
Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms.
Nat Commun.
2022 Apr; 13:2073.
Figure 5.
Top: BRDTBD1-directed BacPROTACs: linking JQ1 to dCymM via different linkers and attachment sites
In summary, as shown in Figure 6: PROTACs induce protein degradation by recruiting E3 ligases that label target proteins for ubiquitination, and finally the proteasome degrades ubiquitinated proteins
Figure 6.
Heterobifunctional approach to protein degradation [5]
No Linker degrader?
In the classification of degradants, molecular glues refer to a class of molecules that also play the role of inducing protein degradation but have no Linker connection, such as Thalidomide, CC-92480, CC-90009 and other structures
.
Molecular glue is closer to traditional small molecules in structure, and has more advantages in membrane permeability and bioavailability.
It is a transformation direction of PROTAC-type degraders
.
Figure 7.
Types of molecular glue and structure of degradant-like molecular glue
Types of molecular glue and structure of degradant-like molecular glue
Degradability evaluation
The ultimate goal of degradants is to degrade the relevant proteins, whether it is PROTAC dependent on the ubiquitinase pathway, LYTAC dependent on the proteasome pathway, or BacPROTAC dependent on the (ClpCP) protease
.
In addition to Kd value determination, Western Blot experiments are more intuitive in verifying protein degradation, so they are often used to test the activity of PROTAC-like molecules
.
Figure 8.
Results of target protein and Western Blot experiments [9]
Results of target protein and Western Blot experiments [9]
Summarize
PROTAC has derived a class of molecules in the mode of "POI ligand-Linker-degradation system guide", which complements the deficiency of PROTAC as a degradation agent in the degradation of certain protein and non-protein molecules, and endows the degradation agent with this role.
Concept more possibilities
.
In addition to the difference between the activity test results and conventional molecules caused by the molecule's own mechanism of action, the appropriate degradation pathway has a particularly great influence on the activity
.
MCE is the world's leading supplier of scientific research chemicals and bioactive compounds.
It can provide scientists with PROTAC related products.
At present, we have various products such as PROTAC, AUTAC, ATTEC, molecular glue and their building blocks online
.
At the same time, we also provide integrated synthesis services for PROTAC products
.
|
ATTEC |
|
LC3-mHTT-IN-AN2 LC3-mHTT-IN-AN2 (Compound AN2) mHTT-LC3 ，LC3-mHTT-IN-AN2 (mHTT) LC3B ， wtHTT |
|
LC3-mHTT-IN-AN1 LC3-mHTT-IN-AN1 (Compound AN1) mHTT-LC3 ，LC3-mHTT-IN-AN1 (mHTT) LC3B ， wtHTT |
|
AUTAC |
|
AUTAC1 AUTAC1 MetAP2 (AUTAC) |
|
AUTAC2 AUTAC2 FKBP12 (AUTAC) |
|
Molecular Glues |
|
Mezigdomide Mezigdomide (CC-92480) is a cereblon E3 ubiquitin ligase modulating drug (CELMoD) that acts as a molecular glue |
|
Eragidomide Eragidomide (CC-90009) is a first-in-class GSPT1-selective cereblon (CRBN) E3 ligase modulator that acts as a molecular glue |
|
FPFT-2216 FPFT-2216 is a "molecular glue" compound that degrades phosphodiesterase 6D (PDE6D), zinc finger transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and casein kinase 1α (CK1α) |
.
references
1.
Jin J, Wu Y, Chen J, Shen Y, Zhang L, Zhang H, Chen L, Yuan H, Chen H, Zhang W, Luan X.
The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination.
Theranostics.
2020 Aug 8;10(22):10141-10153.
2.
Fischer F, Alves Avelar LA, Murray L, Kurz T.
Designing HDAC-PROTACs: lessons learned so far.
Future Med Chem.
2022 Jan;14(3):143-166.
3.
Pettersson M, Crews CM.
PROteolysis TArgeting Chimeras (PROTACs) - Past, present and future.
Drug Discov Today Technol.
2019 Apr;31:15-27.
4.
Ahn G, Banik SM, Miller CL, Riley NM, Cochran JR, Bertozzi CR.
LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation.
Nat Chem Biol.
2021 Sep;17(9):937-946.
5.
Fu Y, Lu B.
Targeting lipid droplets for autophagic degradation by ATTEC.
Autophagy.
2021 Dec;17(12):4486-4488.
6.
Morreale FE, Kleine S, Leodolter J, Junker S, Hoi DM, Ovchinnikov S, Okun A, Kley J, Kurzbauer R, Junk L, Guha S, Podlesainski D, Kazmaier U, Boehmelt G, Weinstabl H, Rumpel K, Schmiedel VM, Hartl M, Haselbach D, Meinhart A, Kaiser M, Clausen T.
BacPROTACs mediate targeted protein degradation in bacteria.
Cell.
2022 Jun 1:S0092-8674(22)00593-1.
7.
Schreiber SL.
The Rise of Molecular Glues.
Cell.
2021 Jan; 184(1): 3-9.
8.
Li Z, Wang C, Wang Z, Zhu C, Li J, Sha T, Ma L, Gao C, Yang Y, Sun Y, Wang J, Sun X, Lu C, Difiglia M, Mei Y, Ding C, Luo S, Dang Y, Ding Y, Fei Y, Lu B.
Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds.
Nature.
2019 Nov;575(7781):203-209.
Grohmann, C.
, Magtoto, CM, Walker, JR et al.
Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms.
Nat Commun.
2022 Apr; 13:2073.
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