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Art. -Nr.: HY-169072

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PROTAC MLKL Degrader-2

PROTAC MLKL Degrader-2 is an orally active and highly selective mixed lineage kinase domain-like pseudokinase (MLKL) PROTAC degrader with a DC₅₀ of 0.012 μM. PROTAC MLKL Degrader-2 recruits the CRBN E3 ubiquitin ligase to form a ternary complex, leading to ubiquitination of MLKL and its degradation via a proteasome-dependent pathway. PROTAC MLKL Degrader-2 inhibits necroptosis, reduces ROS production, restores mitochondrial function, and ameliorates lysosomal dysfunction induced by necroptotic stimuli. PROTAC MLKL Degrader-2 degrades MLKL in xenograft mouse models. PROTAC MLKL Degrader-2 can be used in cancer-related research.
(Pink: Mixed Lineage Kinase ligand (HY-169073); Blue: Cereblon ligand (HY-14658); Black: linker).

Nur für Forschungszwecke. Wir verkaufen nicht an Patienten.

CAS. Nr.: 3103327-20-1
Formel: C₃₆H₃₅N₉O₉S
Molecular Weight:769.78

Speicherung:

Please store the product under the recommended conditions in the Certificate of Analysis.

Data Sheet (275 KB)

PROTAC MLKL Degrader-2 Chemical Structure

CAS. Nr.: 3103327-20-1

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Biologische Aktivität
- Beschreibung
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- Parmacokinetics
- In Vivo
Chemical Information
Reinheit & Dokumentation
Verweise
Calculators
Help & FAQs
Classifications
Bioz

Biologische Aktivität

Beschreibung

PROTAC MLKL Degrader-2 is an orally active and highly selective mixed lineage kinase domain-like pseudokinase (MLKL) PROTAC degrader with a DC₅₀ of 0.012 μM. PROTAC MLKL Degrader-2 recruits the CRBN E3 ubiquitin ligase to form a ternary complex, leading to ubiquitination of MLKL and its degradation via a proteasome-dependent pathway. PROTAC MLKL Degrader-2 inhibits necroptosis, reduces ROS production, restores mitochondrial function, and ameliorates lysosomal dysfunction induced by necroptotic stimuli. PROTAC MLKL Degrader-2 degrades MLKL in xenograft mouse models. PROTAC MLKL Degrader-2 can be used in cancer-related research^[1]. (Pink: Mixed Lineage Kinase ligand (HY-169073); Blue: Cereblon ligand (HY-14658); Black: linker).

IC₅₀ & Target

MLKL^[1]

Alle PROTACs Isoform-spezifische Produkte anzeigen :

Cellular Effect

Cell Line	Type	Value	Description	References
HT-29	EC₅₀	0.017 μM Compound: MP-11	Anti-necroptotic activity against TSZ-treated human HT-29 cells assessed as cell survival incubated for 24 hrs by CCK8 assay Anti-necroptotic activity against TSZ-treated human HT-29 cells assessed as cell survival incubated for 24 hrs by CCK8 assay	[PMID: 39180479]
HT-29	EC₅₀	0.019 μM Compound: MP-11	Anti-necroptotic activity against TSZ-treated human HT-29 cells assessed as cell survival incubated for 4 hrs followed by fresh medium replacement without compound by CCK8 assay Anti-necroptotic activity against TSZ-treated human HT-29 cells assessed as cell survival incubated for 4 hrs followed by fresh medium replacement without compound by CCK8 assay	[PMID: 39180479]
HT-29	IC₅₀	>40 μM Compound: MP-11	Cytotoxicity against human HT-29 cells Cytotoxicity against human HT-29 cells	[PMID: 39180479]

In Vitro

PROTAC MLKL Degrader-2 (MP-11) covalently binds to the Cys86 residue of recombinant human MLKL protein via loss of its methanesulfonyl group, and exhibits extremely high whole-proteome selectivity for MLKL in HT-29 cells^[1].
PROTAC MLKL Degrader-2 (24 h) degrades MLKL in HT-29 cells, with a DC₅₀ of 0.012 μM and a maximum degradation rate of 95.06%^[1].
PROTAC MLKL Degrader-2 (0.01-10 μM; 24 h) potently and selectively protects human HT-29 and U937 cells from necroptosis (EC₅₀ = 0.017 μM in HT-29 cells), but has no effect on mouse cells or apoptosis^[1].
PROTAC MLKL Degrader-2 (10-300 nM) reduces the proportion of PI-positive necrotic HT-29 cells in a dose-dependent manner^[1].
PROTAC MLKL Degrader-2 (10-300 nM; 0-12 h) efficiently degrades MLKL in HT-29 cells in a dose- and time-dependent manner in vitro, with rapid degradation activity and no effect on the upstream RIPK1 signaling pathway^[1].
PROTAC MLKL Degrader-2 acts as a covalent MLKL degrader in HT-29 cells, retains activity after washout, and inhibits MLKL expression and trimerization for an extended period^[1].
PROTAC MLKL Degrader-2 (1 μM; 6 h) inhibits the expression of pMLKL and prevents lysosomal membrane permeabilization in HT-29 cells treated with TSZ^[1].
PROTAC MLKL Degrader-2 dose-dependently reduces ROS production and restores mitochondrial function in TSZ-treated HT-29 cells^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Viability Assay^[1]

Cell Line:

human HT-29 colon adenocarcinoma cells, human U937 histiocytic lymphoma cells, mouse J774A.1 macrophage cells, mouse L929 fibroblast cells
Concentration:

0.01, 0.03, 0.1, 0.3, 1, 3, 10 μM
Incubation Time:

24 h
Result:

Protected HT-29 and U937 human cells from TSZ-induced necroptosis in a dose-dependent manner, with an EC₅₀ of 0.017 μM in HT-29 cells.
Showed no protective effect on mouse J774A.1 and L929 cells.
Showed no dose-dependent protective effect against TS-induced apoptosis in HT-29 cells.

Western Blot Analysis^[1]

Cell Line:

HT-29 cells
Concentration:

30 nM
Incubation Time:

0, 1, 2, 4, 8, 12 h
Result:

Caused dose-dependent degradation of MLKL in TSZ-treated HT-29 cells, with 30 nM MP-11 almost eliminating MLKL expression, without altering RIPK1 or pRIPK1 levels.
Under necroptotic conditions, MLKL showed marked degradation 2 h after MP-11 treatment, reaching ~95% degradation by 12 h.
Under normal conditions, MLKL was degraded within 2 h of MP-11 treatment, reaching ~90% degradation by 12 h.

Immunofluorescence^[1]

Cell Line:

HT-29 cells
Concentration:

1 μM
Incubation Time:

6 h
Result:

Markedly decreased pMLKL expression and restored normal LAMP2 localization, indicating preserved lysosomal function.

Parmacokinetics

Species	Dose	Route	T_max	T_1/2	C_max	AUC_0-t	CL	Bioavailability
Mice^[1]	40 mg/kg	i.v.	0 h	0.26 h	3230.9 ng/mL	1558.5 ng·h/mL	25749.8 mL/h/kg	/
Mice^[1]	40 mg/kg	p.o.	0.18 h	0.22 h	633.8 ng/mL	401.2 ng·h/mL	98141.8 mL/h/kg	25.7 %

In Vivo

PROTAC MLKL Degrader-2 (MP-11) (40 mg/kg; i.v., p.o.; single dose) effectively degrades MLKL in HT-29 xenograft tumors in vivo, with ~90% degradation via intravenous administration and ~72% degradation via oral administration at a single 40 mg/kg dose, while exhibiting good in vivo safety^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:

BALB/c nude (female, 4 weeks old, specified pathogen-free grade)^[1]
Dosage:

40 mg/kg (i.v.)
40 mg/kg (p.o.)
Administration:

i.v.; single dose
p.o.; single dose
Result:

Caused an ~90% MLKL degradation rate in xenograft tumors.
Caused an ~72% MLKL degradation rate in xenograft tumors.
Reached tumor tissue concentrations of 224.2 ng/g at 1 hour post-administration and 176.18 ng/g at 24 hours post-administration via intravenous route.
Reached tumor tissue concentrations of 80.22 ng/g at 1 hour post-administration and 74.18 ng/g at 24 hours post-administration via oral route.
Showed no obvious side effects or major organ damage via either administration route.
Caused only a minor, transient body weight decrease in the initial 2 days via intravenous route.

Chemical Information

CAS. Nr. 3103327-20-1
Molecular Weight 769.78
Formel C₃₆H₃₅N₉O₉S
SMILES

O=C(NC1=CC=CC(C#CCN(C(N(C2=O)C)=O)C3=C2N(C(S(C)(=O)=O)=N3)C)=C1)CN4CCN(C5=CC6=C(C=C5)C(N(C6=O)C7CCC(NC7=O)=O)=O)CC4
Versand

Room temperature in continental US; may vary elsewhere.
Speicherung

Please store the product under the recommended conditions in the Certificate of Analysis.

Reinheit & Dokumentation

Select Batch:

Reinheit: 99.98%

Assay: 99.98%

ee.: 99.98%

Data Sheet (275 KB)
COA (2659 KB)
Elemental Analysis Report (2659 KB)
HNMR (2659 KB)
CNMR (2659 KB)
RP-HPLC (2659 KB)
NP-HPLC (2659 KB)
MS (2659 KB)
LCMS (2659 KB)
IR (2659 KB)
GC (2659 KB)
OR (2659 KB)
SDS-PAGE (2659 KB)
SEC-HPLC (2659 KB)
Other Report (2659 KB)
Handling Instructions (2659 KB)

Verweise

[1]. Li S, et al. Discovery of Covalent MLKL PROTAC Degraders via Optimization of a Theophylline Derivative Ligand for Treating Necroptosis. Journal of medicinal chemistry. 2024 Sep 12;67(17):15353-15372. [Content Brief]

Calculators

Molaritätsrechner

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

Mass Mass

Konzentration Konzentration

Volumen Volumen

Molecular Weight Molecular Weight

Verdünnungsrechner

Konzentration _{(Stammlösung)} × Volumen _{(Stammlösung)} = Konzentration _{(Ziellösung)} × Volumen _{(Ziellösung)}

Konzentration _{(Stammlösung)} Konzentration _{(Stammlösung)}

Volumen _{(Stammlösung)} Volumen _{(Stammlösung)}

Konzentration _{(Ziellösung)} Konzentration _{(Ziellösung)}

Volumen _{(Ziellösung)} Volumen _{(Ziellösung)}

Help & FAQs

How should lyophilized recombinant proteins be reconstituted and stored?

1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

MOQ

Minimum order quantity

100 mg

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Biologische Aktivität
- Beschreibung
- IC₅₀ & Target
- In Vitro
- In Vivo
Chemical Information
Reinheit & Dokumentation
Verweise

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PROTAC MLKL Degrader-2

Alle PROTACs Isoform-spezifische Produkte anzeigen

Biologische Aktivität

Chemical Information

Reinheit & Dokumentation

Verweise

Calculators

Help & FAQs

PROTAC MLKL Degrader-2 Related Classifications

HY-169072 Related Classifications