KW-6356

KW-6356 : Inverse agonist of ADORA2A

Structure

SERP Rating

In Cells

(1 ratings)

In Model Organisms

(0 ratings)

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Probe KW-6356 is in the process of SERP review.

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Information

ADORA2A

Inverse Agonist

up to 100 nM

In Vitro Validations

Uniprot ID: P29274

Target Class: GPCR

Target SubClass: Adenosine receptor

Potency: Kd

Potency Value: 0.13 nM

Potency Assay: [3H]-KW-6356 binding to human A2A receptor

PDB ID for probe-target interaction (3D structure): 8GNE

Target aliases:

Adenosine receptor A2a, ADORA2, ADORA2A, AA2AR_HUM ...

DOI Reference: 10.1124/molpharm.122.000633

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay, off target (cells): In vitro binding assays using selective radioactively labeled ligands with 10 µM of KW-6356 were performed in order to determine the affinity to other receptors, transporters, and ion channels. KW-6356 showed weak affinity in vitro for other receptors, transporters, and ion channels. Inhibition rates (%) of KW-6356 for MAO-A, MAO-B, and COMT were 1.40, 4.01, and 2.22, respectively, at 10 µM.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

KW-6356 (also known as Sipagladenant) has excellent potency against Adenosine A2A (mouse/rat/dog/marmoset/human pKi of 9.49/10.0/9.55/9.95/9.93 respectively). It shows good selectivity between Adenosine receptors (at least >100-fold). The highest affinities for off-target receptors are mouse adenosine A1 (pKi = 7.51) and human adenosine A2B (7.49). At 10 uM, KW-6356 shows only weak inhibition (<30%) against members of a panel of various receptors, transporters and ion channels with the exception of 50.1% inhibition of dopamine receptor d5. Further, KW-6356 displays insignificant inhibition of dopamine metabolising enzymes MAO-A, MAO-B and COMT. The functional effect of KW-6356 has been reported by monitoring in cAMP levels in cells. The compound shows inverse agonism (pEC50 of 8.46) in HEK293 and time-dependence studies indicate insurmountable antagonism (Namalwa cells). The compound is orally available and has been taken into in vivo efficacy studies for Parkinson's in marmosets and has entered clinical trials in humans as far as Phase 2b, however despite indicating positive results, Kyowa Kirin have discontinued the development of KW-6356. This is a well-characterised, highly-selective probe.

(last updated: 9 Jan 2024 )