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Skepinone-L

ATP-competitive inhibitor of MAPK14

Structure

Information

  • MAPK14
  • ATP-competitive inhibitor
  • 100-400 nM

In Vitro Validations

Uniprot ID: Q16539
Target Class: Kinase
Target SubClass: CMGC
Potency: Kd
Potency Value: 1.5 nM
Potency Assay: Ambit Biosciences binding assay
PDB ID for probe-target interaction (3D structure): 3ZYA,  3QUE
Structure-activity relationship: Yes, see J Med Chem paper
Target aliases:
Mitogen-activated protein kinase 14, SAPK2A, MXI2, ...

DOI Reference: 10.1038/nchembio.761

Uniprot ID: Q16539
Target Class: Kinase
Target SubClass: CMGC
Potency: IC50
Potency Value: 5 nM
Potency Assay: In enzyme activity assays
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Mitogen-activated protein kinase 14, SAPK2A, MXI2, ...

DOI Reference: 10.1038/nchembio.761

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): In a panel of 402 kinases at 1 uM, no notable activity was detected other than for p38 MAPK alpha and beta. Comparable results were obtained in ProQinase GmbH panel of 333 kinases.
Potency assay, off target (cells): Skepinone-L did not affect phosphorylation of c-Jun or CREB.
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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

Skepinone-L is a potent, selective, and cell active p38 inhibitor. It is orally bioavailable in mice. It shows exquisite kinase selectivity, as measured by screening against broad panels at Ambit (DiscoveRx) and ProQinase. Part of this selectivity arises from the design of the molecule to take advantage of the so-called "glycine flip", which can only occur in a small subset of kinases.

(last updated: 18 Mar 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

Experiments for selectivity in cells included an Ambit screen and a ProQuinase panel. Structure-activity relationships are logical and structurally based. I would like to see evidence for and against off-targets beyond kinases, but otherwise this is a potent, orally bioavailable probe with very good selectivity. A careful metabolism study was reported in DOI: 10.1039/C4MD00106K.

(last updated: 2 Apr 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

Skepinone-L is a potent (5 nM) p38alpha/beta-dual inhibitor with wonderful kinome selectivity (minimal to no activity on 300+ kinases at 1 uM). It has activity in a cell-based, mechanistic assay at 25 nM and relevant phenotypic assay at 30-50 nM, and showed reduction of a relevant biomarker when dosed orally in mice at 3 mg/kg. A smooth sigmoidal dose response in the mechanistic assay suggests no cytotoxicity at the high dose of 10 uM, though its unclear of HSP27 phosphorylation in the time frame of the assay is a good indicator of cytotoxicity. Dose response was not reported for phenotypic endpoints. In vitro metabolism reported elsewhere suggests comparable PK in rat and some gender differences in both species, but these findings have not been confirmed in vivo. This appears to be a good tool for research, with the caveat that there may be better characterized tools for chronic, in vivo dosing available among the many clinical assets that have been disclosed, including SCIO-469/talmapimod (even more selective), VX-702, VX-745, losmapimod, dilmapimod, pamapimod, etc. For most of those molecules, more chronic, disease-relevant endpoints have been reported, and by virtue of their administration to humans, we can implicitly assume they have a relatively clean tox history in rodents at doses above the therapeutic dose (if not explicitly reported). If selectivity over p38beta is required for in vitro experiments, SX-011 appears to be the most selective tool available (~250X selective for p38alpha over beta).
 

(last updated: 2 Jun 2017 )