Entospletinib

Inhibitor of SYK

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

Inhibitor

up to 1 uM

Probe Availability:

In Vitro Validations

Uniprot ID: P43405

Target Class: Protein kinase

Target SubClass: TK

Potency: IC50

Potency Value: 7.7 nM

Potency Assay: SYK enzymatic assay (Lance-based assay)

PDB ID for probe-target interaction (3D structure): 4PUZ

Structure-activity relationship: yes

Target aliases:

Tyrosine-protein kinase SYK, SYK, KSYK_HUMAN, p72- ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

Profiled using the KinomeScan platform against a panel of 359 nonmutant kinases at a single concentration of 10 μM. Kd values were determined for 67 kinases and only TNK1 showed less than 10-fold selectivity versus Syk.

Potency assay, off target (cells): target protein phosphorylation assay

Probe Selectivity in Cell:

In cells, Entospletinib inhibited Flt3, Jak2, c-Kit, KDR, and Ret with 13- to >1000-fold cellular selectivity for Syk as assessed by target protein phosphorylation or functional response.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Although quite selective, it is important to note that cellular effects of Jak2, ckit, and Flt3 inhibition are seen at EC50 values of 330-450 nM. If these kinases may be relevant to the pathway of interest, it will be important to stick to lower concentrations of the probe to avoid confusion. I would not recommend going above 1 uM in cells given the activity against other kinases. Regarding in vivo use in rats, although reduction of ankle inflammation was observed when dosed orally at 1 mg /kg bid, other anti-inflammatory effects were less prominent until dosing at 3 mg/kg, and the molecule was tested up to 10 mg/kg in rats.

(last updated: 4 Aug 2021 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Entospletinib required formulation in NMP/PEG-400 to determine its PK in CD1 mice due to its poor solubility. This solubility needs to be improved to improve its utility in vivo.

(last updated: 26 Aug 2021 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Reviewer recommended dose in vivo: use both 1 mg/mL and 3 mg/mL dosing regimen for in vivo studies as higher dose resulted in at least 50% target coverage (pSyk EC50).

(last updated: 13 Sept 2021 )