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BAY-549

BAY-549 : Inhibitor of ROCK1, ROCK2

Structure

Information

  • ROCK1
  • ROCK2
  • Inhibitor
  • up to 100 nM
  • Reviewer recommended concentration: 0.5 to 1 uM

In Vitro Validations

Uniprot ID: Q13464
Target Class: Kinase
Target SubClass: AGC
Potency: IC 50
Potency Value: 0.6 nM
Potency Assay: biochemical ROCK assay
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: yes
Target aliases:
Rho-associated protein kinase 1, ROCK1, ROCK1_HUMA ...

DOI Reference: 10.1038/sj.bjp.0707484

Uniprot ID: Q13464
Target Class: Kinase
Target SubClass: AGC
Potency: Ki
Potency Value: 3.7 nM
Potency Assay: Functional inhibition: IC50 (pMBS, human)
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Rho-associated protein kinase 1, ROCK1, ROCK1_HUMA ...

DOI Reference: 10.1038/sj.bjp.0707484

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 Trk-A 252 nM, Flt3 303 nM
Potency assay (off target): Kinase panel
Probe Selectivity in Vitro:
Selectivity >250 fold vs all other kinases (Upstate panel @ 10 µM) Clean GPCR scan except for activity on OPRK1 (Ki = 187.33 nM) and SIGMAR1 (Ki = 6765.5 nM)
Probe Selectivity in Cell:
LeadProfilingScreen closest off-targets @ 10 µM: SLC6A3 (DAT, human) IC50 = 0.4 µM
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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

The selectivity screening only included 112 kinases, data not supplied. It is possible that wider screening would identify additional inhibited kinases, albeit that the closest relatives to ROCK1 and ROCK2 (MRCKs) have only ~38% sequence identity over the kinase domain.

(last updated: 7 Jun 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This compound is also called ROCK-IN-2, Azaindole 1, Azaindole 1, TC-5 7001 and the CAS No. is 867017-68-3

Schirok et al ChemMedChem 3 (2008) 1893 – 1904 (Cmpd 32)

SAR development? Yes, clear SAR with optimization.

ROCK-2 IC50 is given as 3 nM.

Arteria saphena IC50 65 nM (functional, rabbit) SAR approximately parallels kinase SAR.

Biomarker pMBS not undertaken.

Medium clearance mice and dogs; t1/2 rats 1.2 h, F 48%.

Kast et al BJP 152 (2020) 1070-1080

IC50 ROCK-1 is given as 0.6 nM.

Functional inhibition: IC50 (pMBS, human) is given as 3.7 nM.

IC50 ROCK-2 is given as 1.1 nM.

Functional inhibition: IC50 (pMBS, human) is given as 4.8 nM.

The compound is ATP-competitive.

Inactive against 89 kinases (IC50 > 10uM), another 21 weakly inhibited with IC50 1-10 uM, only 2 sub-uM IC50 (TRK 252 nM, FLT3 303 nM).

Inactive against 60 relevant cardiovascular enzymes/receptors and weak activity just against L-type calcium channel (6.7 uM) and sodium channel (6.8 uM).

Highly bioavailable rats, dogs (approximately 50%-75%).

(last updated: 28 Jun 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

BAY-549, also known as compound 32 in Schirok H, et al ChemMedChem 2008, or Azaindole 1 in Kast R, et al  Br J Pharmacol 2007, is a high quality tool compound for ROCK1/2. It is active in rabbit isolated artery assay and reduces blood pressure when dosed in rats and dogs. The only limitation is that kinome selectivity data are limited to a panel of 112 kinases (Upstate), so it remains possible that the compound may have off-target kinase activities outside the tested panel.  That said, ROCK1/2 kinases have unique active site structure as noted in the paper, so this is an unlikely scenario. Regardless, it would be prudent to test multiple  ROCK1/2 inhibitors from orthogonal chemical scaffolds, for example also GSK429286A (https://lincs.hms.harvard.edu/db/datasets/20030/main). 

(last updated: 24 Mar 2021 )