BMS-911543

Reagent Authentication Certificate:

Chemical Probes Portal BMS-911543.pdf

Protein target name:

JAK2

Mechanism of action:

ATP-competitive inhibitor

Recommended Concentration for use in cells:

Up to 200 nM

Probe Availability

MedChem Express (1271022-90-2)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:6192

Entrez gene ID:

3717

UNIPROT ID:

O60674

Target alias:

JTK10, THCYT3

Probe Details

Chemical Probes Portal ID:

CPP563

Probe alias:

JTK10, THCYT3, ENSG00000096968, BMS911543

PubChem CID:

50922691

ChEMBL ID:

CHEMBL3545215

SMILES string:

CCN1C(=CC2=C3C(=C(N=C21)NC4=NN(C(=C4)C)C)N=CN3C)C(=O)N(C5CC5)C6CC6

InChi Key:

JCINBYQJBYJGDM-UHFFFAOYSA-N

Control compound:

Not available

Orthogonal probe:

XL019AZ-960Gandotinib

Physico-chemical properties

Solubility - preferred solvent:

DMSO

NMR:

1H-NMR (400 MHz, CDCl3) δ 8.06 (s, 1 H), 7.62 (s, 1 H), 6.94 (s, 1 H), 6.85 (s, 1 H), 4.66 (q, 2 H, J =
7.12 Hz), 3.98 (s, 3 H), 3.72 (s, 3 H), 2.78 - 2.88 (m, 2 H), 2.33 (d, 3 H, J = 0.44 Hz), 1.49 (t, 3 H, J =
7.15 Hz), 0.81 - 0.89 (m, 4 H), 0.71 - 0.78 (m, 4 H).

13C NMR (126MHz, CDCl3) δ 167.4, 147.7, 144.4, 144.1, 139.1, 138.8, 133.5, 126.4, 124.6, 101.0,
98.3, 96.1, 38.9, 35.4, 32.6, 31.3, 15.8, 11.5, 9.0

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

JAK2: 0.48 nM

Potency assay:

IC50=1.1 nM Potency was determined with ATP=Km for each JAK kinase using Caliper LabChip

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

5CF8

Structure-activity relationship:

Yes

Off target activity

Potency (off target):

IC50

Off target protein and potency:

JAK1 360 nM (Ki=110 nM)JAK3 75 nM (Ki=360 nM)TYK2 66 nM

Potency assay (off target):

Potency was determined using ATP at the Km for each JAK kinase using Caliper LabChip

Probe Selectivity in Vitro:

Ambit kinome profiling was done against 451 kinases; Targets with measured IC50s in a biochemical assay are: FLT3 IC50 280 nM, PKA IC50 550 nM, SRC IC50 3640 nM, LYN IC50 300 nM, BMX IC50 1390 nM, c-FMS IC50 450 nM, IKKe IC50 2000 nM, DAPK1 IC50 2320 nM. Selectivity against safety panel of 45 targets (details not known), only active target is PDE4, IC50=5.6 μM.

In cell validation

On target activity in cells

Potency in cells:

IC50

JAK2 60 nM

Potency assay (cells):

JAK2-dependent cell lines SET-2 IC50=60 nM, BaF3-V617F IC50=61 nM JAK 1/3 IL-2-mediated, T-cell proliferation assay IC50=990 nM SET-2 and BaF3-V617F proliferation are dependent on JAK2.

Target engagement assay (cells):

Measurement of STAT5 in SET-2 as well as BaF3-V617F cells; STAT5 is directly downstream from JAK2, with inhibition of 70-80 nM, correlating well with cellular function and enzyme inhibition if the IC50 is corrected for the cellular concentration of ATP.

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

BMS-911543 was not mutagenic or clastogenic in exploratory Ames or in vitro micronucleus assays, respectively

In vivo validation

Organism:

mouseratdogcyno

Dose:

1-100 mg/kg

Route of delivery:

Intravenous

Other route of delivery:

Oral

Plasma half life:

mouse/rat 5 h, dog/cyno 2.2-2.4 h

Systemic clearance:

0.55 (mouse), 0.7 (rat), 6.3 (dog), 5.3 (cyno)

Fraction of probe bound to plasma protein:

Not available

Primary Reference

Reference (doi):

10.1021/acsmedchemlett.5b00226

Reference (PMID):

26288683

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

BMS-911543 is a reversible, pyrrolopyridine ATP-competitive JAK2 inhibitor with high selectivity (JAK2 IC50 =1.1 nM vs JAK1, JAK3, Tyk2 IC50 = 360, 75, 66 nM respectively and SET2 IC50 = 60 nM). In JAK-dependent cells, BMS-911543 causes an anti-proliferative effect with an IC50 in SET2 of 60 and in Ba/F of 370 nM. In an IL-2-dependent T-cell proliferation assay, IC50 = 990 nM (JAK1/3). BMS-911543 suppressed the pSTAT5 levels (mediated by wild-type JAK2) relative to vehicle control when stimulated with thrombopoetin (TPO) in a mouse pharmacodynamic model. BMS-911543 has limited activity in murine model of JAK2(V617F)-driven myeloproliferative neoplasm (doi:10.1016/j.exphem.2015.03.006).

Aug 17 2016 - 7:30pm

BMS-911543 has a favorable profile in an in vitro panel of 45 targets, wherein no activity (IC50 >25 uM) was observed for all targets except PDE4 (IC50: 5.6 uM). No HepG2 cyctotoxicity is observed. BMS-911543 is well tolerated up to 100 mg/kg in rats (single dose).

Sep 8 2016 - 10:03pm

High selectivity for JAK2 over all the other family members (JAK1, JAK3 and TYK2) differentiates this compound from other JAK inhibitors. Overall kinase selectivity is excellent, and a full KinomeScan panel dataset is published. Functional cellular assays confirm that JAK2-dependent pathways are specifically inhibited.

Jan 18 2017 - 12:05pm

BMS-911543

Probe Availability

Probe Information

Target Details

JTK10, THCYT3

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?

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BMS-911543

Probe Availability

Probe Information

Target Details

JTK10, THCYT3

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?