Name: JH-XI-10-02
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Solubility

Soluble in DMSO

Appearance

Yellow Solid

Storage

Store at -20°C

Shipping

Room temperature in continental US; may vary elsewhere

IUPACName

3-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]-N-[(3S,5S,8R,9S,10S,13S,14S,17S)-17-isoquinolin-7-yl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]-N-methylpropanamide

Synonyms

JH XI-10-02; JH-XI 10-02; JH-XI-10 02; JH XI 10 02; JHXI1002; 4,7,10,13-Tetraoxapentadecanamide, 15-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]-N-[(3β,5α,17β)-17-(7-isoquinolinyl)androstan-3-yl]-N-methyl-; 15-[[2-(2,6-Dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]-N-[(3β,5α,17β)-17-(7-isoquinolinyl)androstan-3-yl]-N-methyl-4,7,10,13-tetraoxapentadecanamide; 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((3S,5S,8R,9S,10S,13S,14S,17S)-17-(isoquinolin-7-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)-N-methyl-3,6,9,12-tetraoxapentadecan-15-amide

Density

1.28±0.1 g/cm3

InChI Key

JECHBTRAPARMGI-GFTKVEOVSA-N

InChI

InChI=1S/C53H69N5O9/c1-52-19-15-38(32-37(52)9-10-39-42-12-11-41(53(42,2)20-16-43(39)52)35-8-7-34-17-21-54-33-36(34)31-35)57(3)47(60)18-23-64-25-27-66-29-30-67-28-26-65-24-22-55-44-6-4-5-40-48(44)51(63)58(50(40)62)45-13-14-46(59)56-49(45)61/h4-8,17,21,31,33,37-39,41-43,45,55H,9-16,18-20,22-30,32H2,1-3H3,(H,56,59,61)/t37-,38-,39-,41+,42-,43-,45?,52-,53+/m0/s1

SMILES

O=C1C=2C=CC=C(NCCOCCOCCOCCOCCC(=O)N(C)C3CCC4(C)C(CCC5C6CCC(C=7C=CC=8C=CN=CC8C7)C6(C)CCC54)C3)C2C(=O)N1C9C(=O)NC(=O)CC9

Mechanism

Target: JH-XI-10-02 selectively targets cyclin-dependent kinase 8, with minimal CDK19 degradation.

Binding site: Its CDK8 ligand binds the ATP-competitive catalytic pocket of CDK8.

Mechanism of action: JH-XI-10-02 is a CRBN-recruiting CDK8 PROTAC derived from a CDK8 inhibitor connected to a cereblon ligand such as pomalidomide. The compound recruits CRL4CRBN to CDK8, promoting ubiquitination and proteasome-dependent degradation without reducing CDK8 mRNA levels. Its selectivity over CDK19 enables more precise interrogation of CDK8-specific biology within mediator kinase module signaling. In experimental studies, JH-XI-10-02 is useful for distinguishing CDK8 catalytic inhibition from protein depletion, analyzing transcriptional pathway consequences, and validating CDK8-dependent cellular phenotypes.

Applications

• PROTAC-Mediated Targeted Degradation: JH-XI-10-02 is designed to facilitate the targeted degradation of specific proteins within cellular systems. By harnessing the ubiquitin-proteasome pathway, this compound effectively directs the destruction of proteins that are otherwise considered "undruggable," enhancing the precision of molecular biology experiments.

• Protein Interaction Studies via PROTAC: Utilizing JH-XI-10-02 allows researchers to investigate protein-protein interactions by selectively degrading one interaction partner. This approach provides insights into the functional dependencies and biological roles of target proteins, thereby advancing the understanding of complex cellular pathways.

• Drug Discovery and Development: JH-XI-10-02 serves as a valuable tool in the early stages of drug discovery, enabling the identification of novel therapeutic targets through its targeted protein degradation mechanism. It aids in validating the potential efficacy of degrading specific proteins involved in disease pathways.

• Mechanistic Studies in PROTAC Research: Employing JH-XI-10-02 in mechanistic studies helps elucidate the pathways and processes involved in PROTAC-mediated protein degradation. Researchers can explore the kinetics and dynamics of target engagement and ubiquitination, providing deeper insights into the efficacy and specificity of PROTACs.

1. Development of highly potent and selective steroidal inhibitors and degraders of CDK8.

Hatcher, J.M., Wang, E.S., Johannessen, L., Kwiatkowski, N., Sim, T. and Gray, N.S., 2018. ACS medicinal chemistry letters, 9(6), pp.540-545.

Cortistatin A is a natural product isolated from the marine sponge Corticium simplex and was found to be a potent and selective inhibitor of CDK8. Many synthetic groups have reported total syntheses of Cortistatin A; however, these syntheses require between 16 and 30 steps and report between 0.012-2% overall yields, which is not amenable to large-scale production. Owing to similarities between the complex core of Cortistatin A and the simple steroid core, we initiated a campaign to design simple, more easily prepared CDK8 inhibitors based on a steroid scaffold that would be more convenient for large-scale synthesis. Herein, we report the discovery and optimization of JH-VIII-49, a potent and selective inhibitor of CDK8 with a simple steroid core that has an eight-step synthesis with a 33% overall yield, making it suitable for large-scale preparation. Using this scaffold, we then developed a bivalent small molecule degrader, JH-XI-10-02, that can recruit the E3 ligase CRL4Cereblon to promote the ubiquitination and proteosomal degradation of CDK8.

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