BAY-985

Inhibitor of TBK1, IKBKE

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

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Information

TBK1
IKBKE

Inhibitor

200 nM

Additional Data

SGC image SGC Chemical Probe Collection

Probe Availability:

In Vitro Validations

Uniprot ID: Q9UHD2

Target Class: Kinase

Target SubClass: Ser/Thr Protein Kinase

Potency: IC 50

Potency Value: 2 nM

Potency Assay: Low ATP-TR-FRET-based kinase activity inhibition assays using recombinant human enzymes.

PDB ID for probe-target interaction (3D structure): 6RSR

Structure-activity relationship: Yes see DOI: 10.1021/acs.jmedchem.9b01460

Target aliases:

Serine/threonine-protein kinase TBK1, NAK, TBK1, T ...

DOI Reference: 10.1021/acs.jmedchem.9b01460

Uniprot ID: Q9UHD2

Target Class: Kinase

Target SubClass: Ser/Thr Protein Kinase

Potency: IC 50

Potency Value: 18 nM

Potency Assay: High ATP-TR-FRET-based kinase activity inhibition assays using recombinant human enzymes.

PDB ID for probe-target interaction (3D structure): 6RSR

Target aliases:

Serine/threonine-protein kinase TBK1, NAK, TBK1, T ...

DOI Reference: 10.1021/acs.jmedchem.9b01460

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

High kinase selectivity for TBK1 and IKBKE (selectivity ratio >100-fold, except for FLT3 with IC50 = 123 nM (75x) and MAP2K5 IC50 = 847 nM (518x) (both Bayer internal kinase panel); STK17A Kd = 74 nM (49x) and MAP3K19 Kd = 9.6 nM (6x) (both DiscoverX); STK17A IC50 = 310 nM (105x) (Eurofins kinase panel) Two hits in the GPCR scan: TMEM97 (Ki =1155.57 nM) and HTR2B (Ki = 1305.2 nM).

Probe Selectivity in Cell:

Clean in Lead Profiling Screen (Eurofins-Panlabs)

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 2 Jun 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 28 Jun 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Take the usual care with kinase inhibitors. IC50 for TBK1 (STK family) of 2nM/30nM for ATP low [10uM]/high [1mM], 2nM for IKKE (=IKBKE, an STK), <<100 nM for YSK-4 (STE family), 123nM FLT3 (a RTK). So pretty good but you couldn’t rule out a YSK-4 effect in cells/in vivo if dose excessive. Cell-based activity (measuring pIRF3) is IC50 74 nM which is good. It is not clear what the appropriate cell or in vivo on-target response is. Oral availability is low (11%, rats) due to high clearance. Nevertheless, it is stated that “Following administration of a single oral dose of 34 at 100 mg/kg to female NMRI nude mice, the exposure was low to moderate, without hints of accumulation after repeated q.d. (once daily) administration. Biochemical IC50 (TBK1) and cell-based IC50 (TBK1/IKKε) were covered by plasma exposure for 10 and 11 h, respectively. However, proliferative IC50 (SK-MEL-2) was ca. threefold higher than Cmax. Oral dosing at 100-200mkg may be appropriate.

(last updated: 8 Dec 2020 )