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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.
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CAS No. : | 214360-73-3 | MDL No. : | MFCD02093721 |
Formula : | C12H18BNO2 | Boiling Point : | - |
Linear Structure Formula : | (CH3)4C2BO2C6H4NH2 | InChI Key : | ZANPJXNYBVVNSD-UHFFFAOYSA-N |
M.W : | 219.09 | Pubchem ID : | 2734620 |
Synonyms : |
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2yl)aniline
|
Chemical Name : | 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
87% | In dichloromethane; at 20℃; for 10h; | To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.0 g, 13.7 mmol) in DCM (70mL), was added acetic anhydride (7.0 g, 68.5 mmol). The reaction mixture was stirred at RT for 10 h. It was then concentrated under reduced pressure and the resulting residue was purified by flash column chromatography over silica gel (PE/EA 1:1, v/v) to give N-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl) acetamide as a yellow solid (3.1 g, 87%). LC-MS (ESI): m/z (M+1)+ = 262.31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 80.0℃; for 14.0h; | The mixture of 4-amino-3-bromo-furo [3,2-c] pyridine (7) (63 mg, 0. 29MOL), 4- (4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (84 mg, 0.38 MMOL), Pd (PPH3) 4 (34 mg, 0.029 MMOL) and sodium carbonate (0.74 ml, 1.5 MMOL) in 3 ml of DME was stirred for 14 hours at 80C. The solvent was removed, and the resultant residue was purified by chromatography on a silica gel column gel to afford the titled compound (55 mg) 1 H NMR (400MHZ, DMSO-d6) ppm 7.82 (d, J = 6. 1 Hz, 1H), 7.77 (s, 1H), 7.15 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 5.8 Hz, 1H), 6.69 (d, J = 8. 3 Hz, 2H), 5.49 (s, 2H), 5.32 (s, 2H). MS: m/z 226 (M+H) + |
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