Name: PROTAC FLT-3 degrader 1
Brand: BOC Sciences
Rating: 5 (1 reviews)

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10 mM in DMSO

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

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Room temperature in continental US; may vary elsewhere

Synonyms

(2S,4R)-1-[(2S)-2-[3-[2-[2-[2-[4-[(5-tert-butyl-1,2-oxazol-3-yl)carbamoylamino]phenyl]imidazo[2,1-b][1,3]benzothiazol-6-yl]oxyethoxy]ethoxy]propanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

InChI Key

IKJBYQODYFQASC-YKCITUTQSA-N

InChI

InChI=1S/C52H61N9O9S2/c1-31-45(71-30-54-31)34-10-8-32(9-11-34)27-53-47(64)40-24-36(62)28-60(40)48(65)46(52(5,6)7)58-44(63)18-19-67-20-21-68-22-23-69-37-16-17-39-41(25-37)72-50-56-38(29-61(39)50)33-12-14-35(15-13-33)55-49(66)57-43-26-42(70-59-43)51(2,3)4/h8-17,25-26,29-30,36,40,46,62H,18-24,27-28H2,1-7H3,(H,53,64)(H,58,63)(H2,55,57,59,66)/t36-,40+,46-/m1/s1

SMILES

CC1=C(SC=N1)C2=CC=C(C=C2)CNC(=O)C3CC(CN3C(=O)C(C(C)(C)C)NC(=O)CCOCCOCCOC4=CC5=C(C=C4)N6C=C(N=C6S5)C7=CC=C(C=C7)NC(=O)NC8=NOC(=C8)C(C)(C)C)O

Mechanism

Target: Targets estrogen receptor alpha (ERα) for experimental targeted protein degradation studies.

Binding Site: Binds the ERα ligand-binding domain and cereblon thalidomide-binding pocket to support productive ternary complex formation.

Mechanism of Action: PROTAC FLT-3 degrader 1 is designed for use in PROTAC or targeted protein degradation experiments directed toward estrogen receptor alpha (ERα). The bifunctional molecule links a target-recognition element to cereblon, promoting proximity between the protein of interest and ubiquitination machinery. Productive ternary-complex formation can drive polyubiquitination and proteasome-dependent target depletion, allowing researchers to compare pharmacological inhibition with protein removal. It is suitable for evaluating degradation potency, kinetics, pathway selectivity, and downstream signaling consequences in engineered or disease-relevant cellular models.

Applications

• PROTAC-Mediated FLT-3 Degradation: PROTAC FLT-3 degrader 1 is specifically designed to target and degrade the FLT-3 protein, a critical kinase in various hematological malignancies. This application is vital for researchers aiming to elucidate the role of FLT-3 in cancer cell survival and to explore novel therapeutic strategies through targeted protein degradation.

• Targeted Degradation in Leukemia Research: By employing PROTAC FLT-3 degrader 1, scientists can effectively degrade FLT-3, facilitating studies on its downstream signaling pathways. This approach is instrumental in understanding the molecular mechanisms driving leukemia progression and identifying potential intervention points for drug development.

• Investigating Resistance Mechanisms: Utilizing PROTAC FLT-3 degrader 1 allows researchers to study resistance mechanisms that arise in response to FLT-3 inhibition. This application aids in uncovering adaptive cellular responses and supports the development of combinatory treatment strategies to overcome therapeutic resistance in cancer.

• Advancing PROTAC Technology: The use of PROTAC FLT-3 degrader 1 exemplifies the advancement of PROTAC technology in targeted protein degradation. Researchers can leverage this tool to optimize degradation efficiency and specificity, contributing to the broader field of targeted therapies and enhancing the understanding of PROTAC design principles.

1. Sunitinib-based Proteolysis Targeting Chimeras (PROTACs) reduced the protein levels of FLT-3 and c-KIT in leukemia cell lines

Jiadai Zhai, Chuang Li, Bingxia Sun, Sinan Wang, Yuting Cui, Qingzhi Gao, Feng Sang Bioorg Med Chem Lett. 2022 Dec 15;78:129041. doi: 10.1016/j.bmcl.2022.129041.Epub 2022 Nov 1.

Proteolysis Targeting Chimeras (PROTACs) based on multi-target inhibitors have been reported several times recently. The advantages of PROTACs technology and the synergistic mechanism of multi-target drugs endow this class of protein degraders with special research significance. Herein, twelve new PROTACs based on Sunitinib and VHL-ligand were synthesized and evaluated for their in vitro anticancer activities. Among them, PROTACs 5 (IC50 = 2.9 ± 1.5 μM) exhibited the most significant antiproliferative activity against HL-60 cells. Western blot results showed that PROTAC 5 reduced the protein levels of FLT-3 and c-KIT in HL-60 cells, and induced the degradation of FLT-3 via the ubiquitin-proteasome system. Moreover, PROTACs 5 and 6 reduced the protein levels of FLT-3 in K562 cells. These results suggest that PROTAC 5 has the potential for further research, especially in combination with small molecule kinase inhibitors to study multidrug resistance of tyrosine kinase inhibitors in cancer treatment.

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