JH-XI-10-02

JH-XI-10-02 : Degrader (PROTAC) of CDK8

Structure

Information

  • CDK8
  • Degrader (PROTAC)
  • 1-5 uM

In Vitro Validations

Uniprot ID: P49336
Target Class: Kinase
Target SubClass: CMGC
Potency: IC50
Potency Value: 159 nM
Potency Assay: Biochemical assay
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Cyclin-dependent kinase 8, CDK8, CDK8_HUMAN, Prote ...

DOI Reference: 10.1021/acsmedchemlett.8b00011

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:
KinomeScan binding analysis against a panel of 468 kinases at a concentration of 10 μM for parent compound JH-VIII-49. High level of selectivity with only four interactions greater than 90% inhibition including CDK19, CDK8, NEK1, and PIKFYVE. Dose–response analysis revealed an IC50 of 8 nM against CDK19 and no inhibition of NEK1 with an IC50 > 10,000 nM. There are currently no commercial enzyme assays for PIKFYVE, hence it was not followed up.
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SERP ratings and comments


SERP Ratings

In Cell Rating

SERP Comments:

I would not view this chemical probe as of sufficient quality to interrogate consequences of CDK8 degradation in cells. No selectivity data is available for either the kinase binding selectivity or, more importantly, degradation selectivity across the proteome in relevant cell models. Most crucially, whilst effects observed are shown to be CRBN and proteasome dependent, there is no control to demonstrate that down regulation of CDK8 is dependent on the molecule binding to CDK8. It also appears that at the proposed concentrations only partially (not possible to assess how partial with current data set) reduce target protein levels, so some context as to why partial degradation would be of interest for functional investigation of the protein function would be ideal.

(last updated: 9 Mar 2022 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

Insufficient degradation data: DCmax, DC50, and degradation selectivity by proteomics are not reported.

(last updated: 31 Oct 2024 )