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製品番号: 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).

商品は「研究用試薬」です。人や動物の医療用・臨床診断用・食品用の製品ではありません。
研究用途以外に使用した場合、当社は一切の責任を負いかねます。

CAS 番号: 3103327-20-1
分子式: C₃₆H₃₅N₉O₉S
分子量:769.78

保管条件:

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

Data Sheet (275 KB)

PROTAC MLKL Degrader-2 構造式

CAS 番号: 3103327-20-1

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数量

Amount: USD 0.00

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生物活性
- 製品説明
- IC₅₀ & Target
- Cellular Effect
- 体外実験
- Parmacokinetics
- 体内実験
化学情報
純度とドキュメンテーション
参考文献
Calculators
Help & FAQs
関連分類
Bioz

生物活性

製品説明

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]

PROTACs アイソフォーム固有の製品をすべて表示 :

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]

体外実験

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 %

体内実験

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.

化学情報

CAS 番号 3103327-20-1
分子量 769.78
分子式 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
輸送条件

Room temperature in continental US; may vary elsewhere.
保管条件

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

純度とドキュメンテーション

バッチを選択:

純度: 99.98%

Assay: 99.98%

ee.: 99.98%

データシート (275 KB)
COA (2659 KB)
元素分析報告書 (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)
取扱説明書 (2659 KB)

参考文献

[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

モル濃度計算機

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

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分子量分子量

希釈計算機

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濃度 _(開始) 濃度 _(開始)

体積 _(開始) 体積 _(開始)

濃度 _(終了) 濃度 _(終了)

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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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生物活性
- 製品説明
- IC₅₀ & Target
- 体外実験
- 体内実験
化学情報
純度とドキュメンテーション
参考文献

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PROTAC MLKL Degrader-2

PROTACs アイソフォーム固有の製品をすべて表示

生物活性

化学情報

純度とドキュメンテーション

参考文献

Calculators

Help & FAQs

PROTAC MLKL Degrader-2 関連分類

HY-169072 関連分類