TBK1 PROTAC 3i

TBK1 PROTAC 3i : Degrader (PROTAC) of TBK1

Structure

Information

Protein target names: TBK1

Mechanism of action: Degrader (PROTAC)

Recommended in-cell concentration:
up to 1 uM

Reviewer recommended in-cell concentration: up to 100 nM

In Vitro Validations

Uniprot ID: Q9UHD2
Target Class: Protein kinase
Target SubClass: Ser/Thr Protein Kinase
Potency: KD
Potency Value: 4.6 nM
Potency Assay: Kd determined at DiscoverX, VHL Binding Assay Based on Fluorescence Polarization
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Serine/threonine-protein kinase TBK1, NAK, TBK1, T ...

In Cell Validations

In Vivo Data

No in Vivo Validations

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SERP ratings and comments


SERP Ratings

In Cell Rating

Comments:

A potent VHL-based PROTAC molecule for TBK1 (DC50 = 12 nM & Dmax = 96%). SAR with the TBK1 binding moiety, linker and VHL binding moiety were demonstrated in the paper. Most TBK1 and VHL target engagement data are based on biophysical binding assays. Interrogation of downstream signalling (pIRF3) was also proven. Selectivity was only determined against ikkε. No broader kinase or proteome wide degradation selectivity available in the paper.

(last updated: 3 Dec 2020 )

SERP Ratings

In Cell Rating

Comments:

TBK1 PROTAC 3i meets most of the chemical probe criteria for a degrader. The researchers have shown evidence of binding to VHL using an FP assay and that an epimeric negative control compound is unable to degrade TBK1. Proteasomal dependence, quantification of target engagement, and degradation by western blot were also demonstrated. In terms of selectivity, PROTAC 3i had no effect on the degradation of IKKe (65% sequence homology to TBK1) despite poor selectivity of the TBK1 ligand. One criteria for degrader probes is a defined time course for degradation. The researchers in this study only looked at 16 hours. It would be beneficial to see a degradation profile across multiple time points. Additionally, the degradation profile of this PROTAC was not assessed proteome-wide and therefore we can not be fully confident of the selectivity of this PROTAC and that PROTAC 3i has no off-target degradation.

(last updated: 8 Dec 2020 )

SERP Ratings

In Cell Rating

(last updated: 6 May 2021 )