JH-XI-10-02 - CAS 2209085-22-1

JH-XI-10-02 is a potent and selective degrader of CDK8, with an IC50 of 159 nM, based on PROTAC. JH-XI-10-02 causes proteasomal degradation, does not affect CDK8 mRNA levels. JH-XI-10-02 shows no effect on CDK19.

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Molecular Formula
Molecular Weight


    • Specification
      • Solubility
        Soluble in DMSO
        Yellow Solid
        Store at -20°C
        Room temperature in continental US; may vary elsewhere
        IUPAC Name
        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
    • Properties
      • Density
        1.28±0.1 g/cm3
        InChI Key
        Canonical SMILES
    • Reference Reading
      • 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.
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