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PROTACs Targeting MLKL Protect Cells from Necroptosis
Rathje, Oliver H. ; Perryman, Lara ; Payne, Richard J. , et al. J. Med. Chem.,2023,66(16):11216-11236. DOI: 10.1021/acs.jmedchem.3c00665 PubMed ID: 37535857
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Abstract: Mixed Lineage Kinase domain-Like pseudokinase (MLKL) is implicated in a broad range of diseases due to its role as the ultimate effector of necroptosis and has therefore emerged as an attractive drug target. Here, we describe the development of PROteolysis TArgeting Chimeras (PROTACs) as a novel approach to knock down MLKL through chem. means. A series of candidate degraders were synthesized from a high-affinity pyrazole carboxamide-based MLKL ligand leading to the identification of a PROTAC mol. that effectively degraded MLKL and completely abrogated cell death in a TSZ model of necroptosis. By leveraging the innate ability of these PROTACs to degrade MLKL in a dose-dependent manner, the quant. relationship between MLKL levels and necroptosis was interrogated. This work demonstrates the feasibility of targeting MLKL using a PROTAC approach and provides a powerful tool to further our understanding of the role of MLKL within the necroptotic pathway.
Purchased from AmBeed: 30100-16-4 ; 4530-20-5 ; 1703808-53-0 ; 2840-26-8 ; 234081-98-2 ; 108466-89-3 ; 1005342-46-0 ; 154775-43-6 ; 214360-73-3 ; 31108-57-3 ; 57294-38-9 ; 234081-98-2 ; 73183-34-3 ; 462100-06-7 ; 187389-52-2 ; 191732-72-6 ; 173405-78-2 ; 154590-35-9 ; 6404-29-1 ; 1807518-63-3 ; 62595-74-8 ; 77383-17-6 ; 1310949-97-3 ; 138563-69-6 ; 138563-68-5 ; 2704620-74-4 ; 2284453-73-0 ; 191732-72-6 ; 181073-79-0 ...More
CAS No. : | 191732-72-6 | MDL No. : | MFCD07772307 |
Formula : | C13H13N3O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GOTYRUGSSMKFNF-UHFFFAOYSA-N |
M.W : | 259.26 | Pubchem ID : | 216326 |
Synonyms : |
CC-5013
|
Chemical Name : | 3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione |
Signal Word: | Danger | Class: | N/A |
Precautionary Statements: | P501-P202-P201-P280-P308+P313-P405 | UN#: | N/A |
Hazard Statements: | H360 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Weigh 2.08g compound 63 (10mmol, 1eq.), add 100mL THF to dissolve, add 3.87g DIPEA (30mmol, 3eq), stir at room temperature for 10min, add 5.70g HATU (15mmol, 1.5eq.), stir at 40C for 30min, add 3.10 g of compound 6 (12 mmol, 1.2 eq.), reacted at 40C for 5 h, cooled to room temperature after the reaction was completed, and rotary-evaporated under reduced pressure to obtain the crude product, separated by silica gel column chromatography (DCM:MeOH=3:1), dried Dried compound 11 white powder 2.56g, yield 60%; |
A451300[ 1243329-97-6 ]
3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride
Reason: Free-salt