Name: TBK1 PROTAC 3i
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Appearance

White Solid

ShelfLife

2 years

Storage

Store at -20°C

IUPACName

(2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Synonyms

L-Prolinamide, N-[2-[3-[4-[3-[4-[[5-bromo-4-[[3-[(cyclobutylcarbonyl)methylamino]propyl]amino]-2-pyrimidinyl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-, (4R)-; N-[(3-{4-[3-(4-{[5-Bromo-4-({3-[(cyclobutylcarbonyl)(methyl)amino]propyl}amino)-2-pyrimidinyl]amino}phenoxy)propoxy]butoxy}propoxy)acetyl]-3-methyl-L-valyl-(4R)-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)benzyl]-L-prolinamide; (2S,4R)-1-((S)-18-(4-((5-bromo-4-((3-(N-methylcyclobutanecarboxamido)propyl)amino)pyrimidin-2-yl)amino)phenoxy)-2-(tert-butyl)-4-oxo-6,10,15-trioxa-3-azaoctadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; Compound 3i

Density

1.312±0.06 g/cm3

InChI Key

QMGHHBHPDDAGGO-IIWOMYBWSA-N

InChI

InChI=1S/C53H74BrN9O9S/c1-36-46(73-35-58-36)38-16-14-37(15-17-38)31-56-49(66)44-30-41(64)33-63(44)51(68)47(53(2,3)4)60-45(65)34-71-28-10-26-69-24-6-7-25-70-27-11-29-72-42-20-18-40(19-21-42)59-52-57-32-43(54)48(61-52)55-22-9-23-62(5)50(67)39-12-8-13-39/h14-21,32,35,39,41,44,47,64H,6-13,22-31,33-34H2,1-5H3,(H,56,66)(H,60,65)(H2,55,57,59,61)/t41-,44+,47-/m1/s1

SMILES

O=C(NC(C(=O)N1CC(O)CC1C(=O)NCC=2C=CC(=CC2)C=3SC=NC3C)C(C)(C)C)COCCCOCCCCOCCCOC4=CC=C(C=C4)NC5=NC=C(Br)C(=N5)NCCCN(C(=O)C6CCC6)C

Mechanism

Target: TBK1 PROTAC 3i selectively targets TANK-binding kinase 1 over IKKε.

Binding site: Its TBK1 ligand binds the ATP-binding catalytic pocket of TBK1 kinase.

Mechanism of action: TBK1 PROTAC 3i is a VHL-recruiting degrader designed to induce near-complete depletion of TANK-binding kinase 1. The compound connects a TBK1-targeting kinase ligand to a von Hippel-Lindau ligand, enabling formation of a TBK1–PROTAC–VHL ternary complex. This proximity promotes ubiquitination and proteasome-mediated degradation of TBK1, with reported selectivity over the closely related kinase IKKε. In research applications, TBK1 PROTAC 3i supports studies of innate immune signaling, KRAS-associated pathway biology, kinase selectivity, degradation kinetics, and differences between kinase inhibition and protein removal.

Applications

• PROTAC-Mediated TBK1 Degradation: TBK1 PROTAC 3i facilitates the selective degradation of TANK-binding kinase 1 (TBK1), enabling researchers to dissect its role in innate immunity and inflammatory pathways. By leveraging the ubiquitin-proteasome system, this tool aids in elucidating TBK1's contribution to cellular signaling cascades.

• Targeted Degradation in Cancer Research: Utilizing TBK1 PROTAC 3i allows for precise modulation of TBK1 levels, offering insights into its involvement in cancer cell survival and proliferation. This application supports the development of targeted therapies by providing a molecular approach to disrupt oncogenic signaling pathways.

• Investigating Autophagy Regulation: TBK1 PROTAC 3i serves as a valuable asset in studying autophagy-related processes. By degrading TBK1, researchers can explore its regulatory effects on autophagic flux, contributing to a deeper understanding of cellular homeostasis and stress responses.

• Elucidating TBK1's Role in Neurodegeneration: This PROTAC enables targeted degradation of TBK1, assisting in the exploration of its potential impact on neurodegenerative diseases. Researchers can utilize this tool to investigate TBK1's involvement in neuronal survival and inflammatory responses within the nervous system.

1. Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1

Andrew P Crew, Kanak Raina, Hanqing Dong, Yimin Qian, Jing Wang, Dominico Vigil, Yevgeniy V Serebrenik, Brian D Hamman, Alicia Morgan, Caterina Ferraro, Kam Siu, Taavi K Neklesa, James D Winkler, Kevin G Coleman, Craig M Crews J Med Chem. 2018 Jan 25;61(2):583-598. doi: 10.1021/acs.jmedchem.7b00635.Epub 2017 Jul 10.

Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that recruit an E3 ligase to a target protein to facilitate ubiquitination and subsequent degradation of that protein. While the field of targeted degraders is still relatively young, the potential for this modality to become a differentiated and therapeutic reality is strong, such that both academic and pharmaceutical institutions are now entering this interesting area of research. In this article, we describe a broadly applicable process for identifying degrader hits based on the serine/threonine kinase TANK-binding kinase 1 (TBK1) and have generalized the key structural elements associated with degradation activities. Compound 3i is a potent hit (TBK1 DC50 = 12 nM, Dmax = 96%) with excellent selectivity against a related kinase IKKε, which was further used as a chemical tool to assess TBK1 as a target in mutant K-Ras cancer cells.

Stock concentration: *

Desired final volume: *

Desired concentration: *

* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂