Name: Pomalidomide-C3-adavosertib
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

>98%

Solubility

Soluble in DMSO

Appearance

Solid Powder

Storage

Store at -20°C

IUPACName

2-(2,6-dioxopiperidin-3-yl)-4-[3-[4-[4-[[1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-3-oxo-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-6-yl]amino]phenyl]piperazin-1-yl]propylamino]isoindole-1,3-dione

Synonyms

4-((3-(4-(4-((2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 1H-Isoindole-1,3(2H)-dione, 4-[[3-[4-[4-[[2,3-dihydro-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-3-oxo-2-(2-propen-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]phenyl]-1-piperazinyl]propyl]amino]-2-(2,6-dioxo-3-piperidinyl)-; 4-[[3-[4-[4-[[2,3-Dihydro-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-3-oxo-2-(2-propen-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]phenyl]-1-piperazinyl]propyl]amino]-2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione; ZNL-02-096

Density

1.409±0.06 g/cm3

InChI Key

LZUDSNUROXNVPH-UHFFFAOYSA-N

InChI

InChI=1S/C42H45N11O6/c1-4-19-51-38(56)29-25-44-41(48-36(29)53(51)33-11-6-10-32(46-33)42(2,3)59)45-26-12-14-27(15-13-26)50-23-21-49(22-24-50)20-7-18-43-30-9-5-8-28-35(30)40(58)52(39(28)57)31-16-17-34(54)47-37(31)55/h4-6,8-15,25,31,43,59H,1,7,16-24H2,2-3H3,(H,44,45,48)(H,47,54,55)

SMILES

CC(C)(C1=NC(=CC=C1)N2C3=NC(=NC=C3C(=O)N2CC=C)NC4=CC=C(C=C4)N5CCN(CC5)CCCNC6=CC=CC7=C6C(=O)N(C7=O)C8CCC(=O)NC8=O)O

Mechanism

Target: Targets WEE1 checkpoint kinase for experimental targeted protein degradation studies.

Binding Site: Binds the WEE1 ATP-binding pocket and cereblon thalidomide-binding domain to support productive ternary complex formation.

Mechanism of Action: Pomalidomide-C3-adavosertib is designed for use in PROTAC or targeted protein degradation experiments directed toward WEE1 checkpoint kinase. 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 Kinase Degradation: Pomalidomide-C3-adavosertib serves as a potent tool for the targeted degradation of kinases, particularly in cancer research. By specifically recruiting adavosertib-bound kinases to the ubiquitin-proteasome system, this PROTAC facilitates the selective removal of aberrant kinase activity, advancing studies on kinase-driven oncogenesis.

• Targeted Degradation in Cell Cycle Regulation: This PROTAC is instrumental in exploring cell cycle regulation by degrading key proteins involved in cell cycle checkpoints. Researchers can utilize it to dissect molecular pathways and identify novel therapeutic targets for diseases characterized by dysregulated cell cycles.

• Selective Protein Degradation in Drug Resistance Studies: Pomalidomide-C3-adavosertib is valuable in investigating mechanisms of drug resistance. By promoting the degradation of proteins implicated in resistance pathways, researchers can elucidate how resistant phenotypes develop and identify potential strategies to overcome therapeutic challenges.

• PROTAC-Enabled Functional Genomics: This compound aids in functional genomics studies by enabling the precise degradation of target proteins. It allows researchers to conduct loss-of-function studies, thereby enhancing the understanding of protein functions and interactions within biological systems.

1. Development and characterization of a Wee1 kinase degrader.

Li, Z., Pinch, B.J., Olson, C.M., Donovan, K.A., Nowak, R.P., Mills, C.E., Scott, D.A., Doctor, Z.M., Eleuteri, N.A., Chung, M. and Sorger, P.K., 2020. Cell chemical biology, 27(1), pp.57-65.

The G1/S cell cycle checkpoint is frequently dysregulated in cancer, leaving cancer cells reliant on a functional G2/M checkpoint to prevent excessive DNA damage. Wee1 regulates the G2/M checkpoint by phosphorylating CDK1 at Tyr15 to prevent mitotic entry. Previous drug development efforts targeting Wee1 resulted in the clinical-grade inhibitor, AZD1775. However, AZD1775 is burdened by dose-limiting adverse events, and has off-target PLK1 activity. In an attempt to overcome these limitations, we developed Wee1 degraders by conjugating AZD1775 to the cereblon (CRBN)-binding ligand, pomalidomide. The resulting lead compound, ZNL-02-096, degrades Wee1 while sparing PLK1, induces G2/M accumulation at 10-fold lower doses than AZD1775, and synergizes with Olaparib in ovarian cancer cells. We demonstrate that ZNL-02-096 has CRBN-dependent pharmacology that is distinct from AZD1775, which justifies further evaluation of selective Wee1 degraders.

2. 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.

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Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂