Name: TD-428
Brand: BOC Sciences
Rating: 5 (1 reviews)

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Solubility

10 mM in DMSO

Storage

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

IUPACName

2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[3-[2-[2-[2-[[3-(2,6-dioxopiperidin-3-yl)-4-oxo-1,2,3-benzotriazin-5-yl]amino]ethoxy]ethoxy]ethoxy]phenyl]acetamide

Synonyms

2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)acetamide; 6H-Thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide, 4-(4-chlorophenyl)-N-[3-[2-[2-[2-[[3-(2,6-dioxo-3-piperidinyl)-3,4-dihydro-4-oxo-1,2,3-benzotriazin-5-yl]amino]ethoxy]ethoxy]ethoxy]phenyl]-2,3,9-trimethyl-, (6S)-; (6S)-4-(4-Chlorophenyl)-N-[3-[2-[2-[2-[[3-(2,6-dioxo-3-piperidinyl)-3,4-dihydro-4-oxo-1,2,3-benzotriazin-5-yl]amino]ethoxy]ethoxy]ethoxy]phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide; TD 428; TD428

Melting Point

109-111°C

Density

1.50±0.1 g/cm3

InChI Key

XEZUBGASURUNMF-CDRRMRQFSA-N

InChI

InChI=1S/C43H43ClN10O7S/c1-24-25(2)62-43-37(24)39(27-10-12-28(44)13-11-27)47-33(40-51-49-26(3)53(40)43)23-36(56)46-29-6-4-7-30(22-29)61-21-20-60-19-18-59-17-16-45-31-8-5-9-32-38(31)42(58)54(52-50-32)34-14-15-35(55)48-41(34)57/h4-13,22,33-34,45H,14-21,23H2,1-3H3,(H,46,56)(H,48,55,57)/t33-,34?/m0/s1

SMILES

CC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)NC4=CC(=CC=C4)OCCOCCOCCNC5=CC=CC6=C5C(=O)N(N=N6)C7CCC(=O)NC7=O)C8=CC=C(C=C8)Cl)C

Mechanism

Target: TD-428 selectively targets BRD4, a bromodomain and extra-terminal family protein.

Binding site: Its JQ1-derived ligand binds the acetyl-lysine pocket of BRD4 bromodomains.

Mechanism of action: TD-428 is a CRBN-recruiting BET PROTAC designed for highly potent BRD4 degradation. It consists of a JQ1-based BRD4 ligand linked to TD-106, a cereblon-recruiting ligand, allowing formation of BRD4–PROTAC–CRBN ternary complexes. This induced proximity promotes BRD4 ubiquitination and proteasome-dependent depletion, enabling suppression of BET-dependent transcriptional programs through protein removal. TD-428 is useful for studying BRD4-specific chromatin regulation, degradation potency, BET family selectivity, and the biological differences between bromodomain occupancy and depletion of the full BRD4 protein.

Applications

• PROTAC-Mediated Cancer Research: TD-428 is employed in cancer research to selectively degrade oncogenic proteins. By harnessing the ubiquitin-proteasome system, it enables researchers to study the effects of targeted protein degradation on tumor cell viability and proliferation, offering insights into potential therapeutic interventions.

• Targeted Degradation in Neurodegeneration: Researchers use TD-428 to investigate the degradation of neurodegenerative disease-related proteins. This facilitates the exploration of protein homeostasis mechanisms and the development of novel strategies for mitigating protein aggregation-associated neurodegenerative disorders.

• Drug Resistance Mechanism Studies: TD-428 aids in understanding drug resistance by degrading proteins implicated in resistance pathways. By elucidating these mechanisms, researchers can identify new targets for overcoming resistance in various therapeutic contexts, enhancing drug efficacy.

• Signal Transduction Pathway Analysis: Utilizing TD-428 allows for the selective degradation of key signaling proteins, enabling the dissection of complex signal transduction pathways. This application is crucial for identifying critical nodes in cellular signaling, advancing the development of targeted therapies.

1. A novel cereblon modulator for targeted protein degradation.

Kim, S.A., Go, A., Jo, S.H., Park, S.J., Jeon, Y.U., Kim, J.E., Lee, H.K., Park, C.H., Lee, C.O., Park, S.G. and Kim, P., 2019. European Journal of Medicinal Chemistry, 166, pp.65-74.

Immunomodulatory drugs (IMiDs) exert anti-myeloma activity by binding to the protein cereblon (CRBN) and subsequently degrading IKZF1/3. Recently, their ability to recruit E3 ubiquitin ligase has been used in the proteolysis targeting chimera (PROTAC) technology. Herein, we design and synthesize a novel IMiD analog TD-106 that induces the degradation of IKZF1/3 and inhibits the proliferation of multiple myeloma cells in vitro as well as in vivo. Moreover, we demonstrate that TD-428, which comprises TD-106 linked to a BET inhibitor, JQ1 efficiently induce BET protein degradation in the prostate cancer cell line 22Rv1. Consequently, cell proliferation is inhibited due to suppressed C-MYC transcription. These results, therefore, firmly suggest that the newly synthesized IMiD analog, TD-106, is a novel CRBN modulator that can be used for targeted protein degradation.

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