Name: dAURK-4
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Solubility

Soluble in DMSO

Storage

Store at -20°C

IUPACName

4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-N-[3-[2-[2-[3-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]propoxy]ethoxy]ethoxy]propyl]-2-methoxybenzamide

Synonyms

4-((9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)amino)-N-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-7,10,13-trioxa-3-azahexadecan-16-yl)-2-methoxybenzamide; Benzamide, 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-N-[16-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]oxy]-15-oxo-4,7,10-trioxa-14-azahexadec-1-yl]-2-methoxy-; 4-[[9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-N-[16-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]oxy]-15-oxo-4,7,10-trioxa-14-azahexadec-1-yl]-2-methoxybenzamide

Density

1.44±0.1 g/cm3

InChI Key

AQMSIRIHYNCQKO-UHFFFAOYSA-N

InChI

InChI=1S/C52H52ClFN8O12/c1-69-39-9-4-8-37(54)45(39)47-36-25-31(53)11-13-33(36)46-30(27-57-47)28-58-52(61-46)59-32-12-14-34(41(26-32)70-2)48(65)56-18-6-20-72-22-24-73-23-21-71-19-5-17-55-43(64)29-74-40-10-3-7-35-44(40)51(68)62(50(35)67)38-15-16-42(63)60-49(38)66/h3-4,7-14,25-26,28,38H,5-6,15-24,27,29H2,1-2H3,(H,55,64)(H,56,65)(H,58,59,61)(H,60,63,66)

SMILES

COC1=CC(NC2=NC=C3CN=C(C4=C(F)C=CC=C4OC)C4=CC(Cl)=CC=C4C3=N2)=CC=C1C(=O)NCCCOCCOCCOCCCNC(=O)COC1=CC=CC2=C1C(=O)N(C1CCC(=O)NC1=O)C2=O

Mechanism

Target: dAURK-4 selectively targets Aurora kinase A, also known as AURKA.

Binding site: Its alisertib-derived ligand binds the ATP pocket of Aurora A kinase.

Mechanism of action: dAURK-4 is a thalidomide-based AURKA PROTAC derived from the Aurora kinase inhibitor alisertib. By linking an AURKA-recognition element to a cereblon-recruiting ligand, dAURK-4 induces proximity between Aurora A and CRL4CRBN ubiquitination machinery, promoting AURKA ubiquitination and proteasome-dependent degradation. This mechanism supports investigation of Aurora A protein functions beyond catalytic inhibition, including mitotic regulation, spindle-associated signaling, and degradation-specific cellular phenotypes. dAURK-4 is useful for studying AURKA dependency, mitotic checkpoint effects, degrader selectivity, and comparative responses to kinase inhibition versus target depletion.

Applications

• PROTAC-Mediated Kinase Degradation: dAURK-4 is designed to facilitate the targeted degradation of Aurora kinase, a critical regulator of cell division. Researchers can employ this PROTAC to study the effects of precise kinase depletion on mitotic processes and cellular proliferation, providing insights into cancer cell biology and potential therapeutic targets.

• Targeted Protein Degradation in Signal Transduction: Utilize dAURK-4 to investigate the role of Aurora kinase in signal transduction pathways. By selectively degrading this kinase, researchers can dissect its involvement in signaling cascades, offering a deeper understanding of its function and potential points of intervention in oncogenic pathways.

• Investigating Protein Stability Mechanisms: dAURK-4 serves as a powerful tool for exploring the mechanisms governing protein stability and degradation. This PROTAC enables the study of ubiquitin-proteasome system dynamics, enhancing our understanding of proteostasis and its implications for disease states characterized by protein dysregulation.

• Cellular Models of Kinase Inhibition: Use dAURK-4 to create cellular models that mimic the effects of kinase inhibition through targeted protein degradation. This approach allows for the examination of downstream biological consequences, aiding in the identification of compensatory pathways and resistance mechanisms in cancer therapy research.

1. Mapping the degradable kinome provides a resource for expedited degrader development.

Donovan, K.A., Ferguson, F.M., Bushman, J.W., Eleuteri, N.A., Bhunia, D., Ryu, S., Tan, L., Shi, K., Yue, H., Liu, X. and Dobrovolsky, D., 2020. Cell, 183(6), pp.1714-1731.

Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ~200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.

2. PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase.

Adhikari, B., Bozilovic, J., Diebold, M., Schwarz, J.D., Hofstetter, J., Schröder, M., Wanior, M., Narain, A., Vogt, M., Dudvarski Stankovic, N. and Baluapuri, A., 2020. Nature chemical biology, 16(11), pp.1179-1188.

The mitotic kinase AURORA-A is essential for cell cycle progression and is considered a priority cancer target. Although the catalytic activity of AURORA-A is essential for its mitotic function, recent reports indicate an additional non-catalytic function, which is difficult to target by conventional small molecules. We therefore developed a series of chemical degraders (PROTACs) by connecting a clinical kinase inhibitor of AURORA-A to E3 ligase-binding molecules (for example, thalidomide). One degrader induced rapid, durable and highly specific degradation of AURORA-A. In addition, we found that the degrader complex was stabilized by cooperative binding between AURORA-A and CEREBLON. Degrader-mediated AURORA-A depletion caused an S-phase defect, which is not the cell cycle effect observed upon kinase inhibition, supporting an important non-catalytic function of AURORA-A during DNA replication. AURORA-A degradation induced rampant apoptosis in cancer cell lines and thus represents a versatile starting point for developing new therapeutics to counter AURORA-A function in cancer.

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