BMS-911543

ATP-competitive inhibitor of JAK2

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

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Information

JAK2

ATP-competitive inhibitor

Up to 200 nM

DOI - 10.1021/acsmedchemlett.5b00226

Probe Availability:

MedChem Express (1271022-90-2)

In Vitro Validations

Uniprot ID: O60674

Target Class: Kinase

Target SubClass: TK

Potency: Ki

Potency Value: 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

Target aliases:

Tyrosine-protein kinase JAK2, JAK2, JAK2_HUMAN, JA ...

DOI Reference: 10.1021/acsmedchemlett.5b00226

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 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.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP 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).

(last updated: 3 Aug 2016 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

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).

(last updated: 18 Jan 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

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.

(last updated: 28 Jun 2017 )