BSJ-03-123

Degrader (PROTAC) of CDK6

Structure

Information

Protein target names: CDK6

Mechanism of action: Degrader (PROTAC)

Recommended in-cell concentration:
200 nM, up to 1 uM

In Vitro Validations

Uniprot ID: Q00534
Target Class: Kinase
Target SubClass: CMGC
Potency: IC50
Potency Value: 8.7 nM
Potency Assay: In vitro kinase inhibition assay CDK6/CyclinD1
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: no
Target aliases:
Cyclin-dependent kinase 6, CDKN6, CDK6, CDK6_HUMAN ...

DOI Reference: 10.1016/j.chembiol.2018.11.006

Uniprot ID: Q00534
Target Class: Kinase
Target SubClass: CMGC
Potency: IC50
Potency Value: 41.6 nM
Potency Assay: In vitro kinase inhibition assay CDK4/CyclinD1
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Cyclin-dependent kinase 6, CDKN6, CDK6, CDK6_HUMAN ...

DOI Reference: 10.1016/j.chembiol.2018.11.006

In Cell Validations

In Vivo Data

No in Vivo Validations

I have extra information to add

SERP ratings and comments


SERP Ratings

In Cell Rating

Comments:

This is a potent and selective CDK6 degrader and I recommend it as a Protac chemical probe.

(last updated: 7 Jan 2021 )

SERP Ratings

In Cell Rating

Comments:

BSJ-03-123 is a selective CDK6 degrader. When used in combination with the negative control compound BSJ-Bump, it can be a useful probe to examine consequences of targeted degradation of CDK6. Given that, at the time of this writing and to the best of my knowledge, no selective inhibitor of CDK6 kinase activity exists (inhibitors hit both CDK6 and the closely related homolog CDK4), BSJ-03-123 represents the only selective small molecule perturbant of CDK6 function. 

Validation included measuring: (1) in vitro inhibitory activity for target of interest (CDK6) as well as in vitro binding to the E3 ligase (cereblon; CRBN); (2) cellular target engagement; (3) cellular ternary complex formation (CDK6/CRBN/BSJ-03-123); (4) evidence that degradation is CRBN dependent;(5) evidence that degradation is proteasome dependent; (6) KINOMEScan to examine whether the PROTAC inhibits any kinases other than the intended target; (7) quantitative proteomics to examine selectivity of the degrader (CDK6 was observed as the only depleted protein among > 5,000 quantified proteins upon 100 nM/1 hr treatment); (8) selective activity against CDK6-dependent cancer cell lines (AML), while not affecting CDK4-dependent cell lines.

Note of caution: BSJ-03-123 seems to be able to effectively and selectively degrade CDK6 at concentrations as low as 100-200 nM and in timeframes as short as 2-3 hrs of treatment. At higher concentrations (1 uM) BSJ-03-123 seems to inhibit activity of off-target kinases (to lesser extent), as measured by the KINOMEScan, and displays the “hook effect” at 2uM. Therefore, I recommend caution if the PROTAC is used at concentrations approaching 1 uM and don’t recommend the use of this PROTAC above 1 uM.

(last updated: 7 Jan 2021 )

SERP Ratings

In Cell Rating

(last updated: 27 Jan 2021 )