PROTAC FLT-3 degrader 4

製品番号: HY-158325: Data Sheet 取扱説明書
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PROTAC FLT-3 degrader 4 is an orally active CRBN-based FLT3-PROTAC degrader that potently induces FLT3-ITD degradation through the ubiquitin-proteasome system. PROTAC FLT-3 degrader 4 shows highly selective to FLT3-ITD mutant acute myeloid leukemia (AML) cells. (Blue: CRBN ligand, Black: linker; Pink: FLT3 inhibitor).

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PROTAC FLT-3 degrader 4 構造式

CAS 番号 : 2956722-48-6

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von Hippel-Lindau (VHL) Cereblon MDM2 cIAP1

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純度とドキュメンテーション
参考文献
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製品説明

IC₅₀ & Target^[1]

Cereblon

Cellular Effect

Cell Line	Type	Value	Description	References
BaF3	IC₅₀	31.3 nM Compound: A20	Antiproliferative activity against mouse Ba/F3 cells expressing FLT3-ITD D835Y mutant incubated for 48 hrs by CCK8 assay Antiproliferative activity against mouse Ba/F3 cells expressing FLT3-ITD D835Y mutant incubated for 48 hrs by CCK8 assay	[PMID: 38655686]
BaF3	IC₅₀	45.1 nM Compound: A20	Antiproliferative activity against mouse Ba/F3 cells expressing FLT3-ITD D835V mutant incubated for 48 hrs by CCK8 assay Antiproliferative activity against mouse Ba/F3 cells expressing FLT3-ITD D835V mutant incubated for 48 hrs by CCK8 assay	[PMID: 38655686]
BaF3	IC₅₀	46.7 nM Compound: A20	Antiproliferative activity against mouse Ba/F3 cells expressing FLT3-ITD Y842H mutant incubated for 48 hrs by CCK8 assay Antiproliferative activity against mouse Ba/F3 cells expressing FLT3-ITD Y842H mutant incubated for 48 hrs by CCK8 assay	[PMID: 38655686]
BaF3	IC₅₀	66.2 nM Compound: A20	Antiproliferative activity against mouse Ba/F3 cells expressing FLT3-ITD F691L mutant incubated for 48 hrs by CCK8 assay Antiproliferative activity against mouse Ba/F3 cells expressing FLT3-ITD F691L mutant incubated for 48 hrs by CCK8 assay	[PMID: 38655686]
HL-60	IC₅₀	>40000 nM Compound: A20	Antiproliferative activity against human HL-60 cells expressing wild-type FLT3 incubated for 48 hrs by CCK8 assay Antiproliferative activity against human HL-60 cells expressing wild-type FLT3 incubated for 48 hrs by CCK8 assay	[PMID: 38655686]
MOLM-13	IC₅₀	147.4 nM Compound: A20	Antiproliferative activity against Sunitinib-resistant human MOLM-13 cells incubated for 48 hrs by CCK8 assay Antiproliferative activity against Sunitinib-resistant human MOLM-13 cells incubated for 48 hrs by CCK8 assay	[PMID: 38655686]
MOLM-13	IC₅₀	169.9 nM Compound: A20	Antiproliferative activity against human MOLM-13 cells incubated for 48 hrs by CCK8 assay Antiproliferative activity against human MOLM-13 cells incubated for 48 hrs by CCK8 assay	[PMID: 38655686]
MOLM-13	IC₅₀	483.6 nM Compound: A20	Antiproliferative activity against Quizartinib-resistant human MOLM-13 cells incubated for 48 hrs by CCK8 assay Antiproliferative activity against Quizartinib-resistant human MOLM-13 cells incubated for 48 hrs by CCK8 assay	[PMID: 38655686]
MV4-11	IC₅₀	39.9 nM Compound: A20	Antiproliferative activity against human MV4-11 cells expressing FLT3-ITD mutant incubated for 48 hrs by CCK8 assay Antiproliferative activity against human MV4-11 cells expressing FLT3-ITD mutant incubated for 48 hrs by CCK8 assay	[PMID: 38655686]
THP-1	IC₅₀	15117.5 nM Compound: A20	Antiproliferative activity against human THP-1 cells expressing wild-type FLT3 incubated for 48 hrs by CCK8 assay Antiproliferative activity against human THP-1 cells expressing wild-type FLT3 incubated for 48 hrs by CCK8 assay	[PMID: 38655686]
U-937	IC₅₀	>40000 nM Compound: A20	Antiproliferative activity against human U-937 cells expressing wild-type FLT3 incubated for 48 hrs by CCK8 assay Antiproliferative activity against human U-937 cells expressing wild-type FLT3 incubated for 48 hrs by CCK8 assay	[PMID: 38655686]

体外実験

PROTAC FLT-3 degrader 4 (compound A20) shows antiproliferative activities against MV4-11 and MOLM-13 cells (IC₅₀ of 39.9 nM and 169.9 nM, respectively)^[1].
PROTAC FLT-3 degrader 4 (0.25-100 nM; 24 h) demonstrates a substantial reduction in FLT3-ITD protein levels in MV4-11 and MOLM-13 cells^[1].
PROTAC FLT-3 degrader 4 (20 nM; 12 h) inhibits FLT3-ITD phosphorylation and its downstream signal mediators including STAT5, S6K, and ERK in MV4-11 and MOLM-13 cells^[1].
PROTAC FLT-3 degrader 4 (20 nM; 12 h) dose-dependently induces cycle arrest in the G1 phase. PROTAC FLT-3 degrader 4 also dose-dependently induces the apoptosis of MV4-11 and MOLM-13 cells^[1].

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

Western Blot Analysis^[1]

Cell Line:	MV4-11 and MOLM-13 cells
Concentration:	0.25 nM, 0.5 nM, 1 nM, 5 nM, 10 nM, 20 nM, 50 nM, 80 nM, 100 nM
Incubation Time:	24 h
Result:	Showed potent FLT3-ITD degradation activity with DC50 values of 7.4 nM and 20.1 nM for MV4-11 and MOLM-13 cells, respectively.

Apoptosis Analysis^[1]

Cell Line:	MV4-11 and MOLM-13 cells
Concentration:	1 nM, 5 nM, 50 nM
Incubation Time:	24 h
Result:	Blocked AML cell cycle in G1 phase and induced apoptosis.

体内実験

PROTAC FLT-3 degrader 4 (compound A20; 1.235-10 mg/kg; po; daily; for 2 weeks) significantly inhibits tumor growth at 1.25 mg/kg. Tumor regression is observed at 5 mg/kg (TGI = 97.5%), and complete regression is observed at 10 mg/kg^[1].
Pharmacokinetic Parameters of PROTAC FLT-3 degrader 4 in Sprague-Dawley rats^[1].
1.19

parameter	iv (1 mg/kg)	po (10 mg/kg)
AUC_0-t (h·ng/mL)	2768.1	14705.3
C_max (ng/mL)	-	1117.5
T_max (h)	-	6.2
T_1/2 (h)	6.5	3.8
V_ss (L/kg)	3.5	5.7
CL (mL/min/kg)	5.5	11.2
F (%)	-	53

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

Animal Model:	Four week old male nu/nu mice injected with MV4-11 cells^[1]
Dosage:	1.25 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg
Administration:	po; daily; for 2 weeks
Result:	Significantly inhibited tumor growth at 1.25 mg/kg.

分子量

736.79

分子式

C₃₉H₄₁FN₈O₆

CAS 番号

2956722-48-6

SMILES

O=C1NC2=CC=C(C=C2/C1=C/C3=C(C(NC(CN4CCN(CC4)CC5CCN(CC5)C6=CC=C7C(N(C(C7=C6)=O)C8CCC(NC8=O)=O)=O)=O)=CN3)C)F

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

取扱説明書 (2659 KB)

参考文献

[1]. Junwei Wang, et al. Discovery of a Novel Orally Bioavailable FLT3-PROTAC Degrader for Efficient Treatment of Acute Myeloid Leukemia and Overcoming Resistance of FLT3 Inhibitors. J Med Chem. 2024 May 9;67(9):7197-7223. [Content Brief]