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BMS-986142 BTK inhibitor

Cat.No.S8381

BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK with an IC50 of 0.5 nM. In a panel of 384 kinases, only five kinases were inhibited by this compound with less than 100-fold selectivity for BTK (TEC, ITK, BLK, TXK and BMX).
BMS-986142 BTK inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 572.60

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Quality Control

Batch: S838101 DMSO]100 mg/mL]false]Water]Insoluble]false]Ethanol]Insoluble]false Purity: 99.76%
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99.76

Solubility

In vitro
Batch:

DMSO : 100 mg/mL (174.64 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 572.60 Formula

C32H30F2N4O4

 Storage (From the date of receipt) 3 years -20°C powder
CAS No. 1643368-58-4 -- Storage of Stock Solutions

Synonyms N/A Smiles CC1=C(C=CC=C1N2C(=O)C3=C(C(=CC=C3)F)N(C2=O)C)C4=C(C=C(C5=C4C6=C(N5)CC(CC6)C(C)(C)O)C(=O)N)F

Mechanism of Action

Targets/IC50/Ki
BTK
(Cell-free assay)
0.5 nM
In vitro

In B cells stimulated through the B cell receptor (BCR), BMS-986142 potently inhibits signaling and functional end points, including calcium flux (IC50 = 9 nM), production of cytokines, proliferation, and surface expression of the costimulatory molecule CD86 (IC50 = 3−4 nM). In T cells, ITK-catalyzed phosphorylation of PLCγ1 stimulated through the T cell receptor (TCR) is at least 45-fold less potently inhibited by this compound than BTK-dependent signaling end points in B cells, as expected based on the 30-fold selectivity for BTK over ITK in the enzymatic assays.
Kinase Assay
Human Recombinant BTK Enzyme Assay
To V-bottom 384-well plates were added test compounds, human recombinant BTK (1 nM), fluoresceinated peptide (1.5 μM), ATP (20 μM), and assay buffer (20 mM HEPES at pH 7.4, 10 mM MgCl2, 0.015% Brij 35 surfactant, and 4 mM DTT in 1.6% DMSO), with a final volume of 30 μL. After incubating at room temperature for 60 min, the reaction was terminated by adding 45 μL of 35 mM EDTA to each sample. The reaction mixture was analyzed by electrophoretic separation of the fluorescent substrate and phosphorylated product. Inhibition data were calculated by comparison to control reactions with no enzyme (for 100% inhibition) and controls with no inhibitor (for 0% inhibition). Dose−response curves were generated to determine the concentration required for inhibiting 50% of BTK activity (IC50). This compound was dissolved at 10 mM in DMSO and evaluated at 11 concentrations.
In vivo

In multispecies pharmacokinetic studies, the absolute oral bioavailability of BMS-986142 is 93% in mice, 67% in rats, 33% in cynomolgus monkeys, and 100% in dogs. The total body plasma clearance of this compound is low in all species. The large steady-state volume of distribution observed is indicative of extravascular distribution, in spite of the high protein binding. However, brain penetration is very low in rats (<5% of plasma concentration). This compound blocks the increase in severe proteinuria in a female NZB/W lupus-prone mouse model in vivo. Treatment with this chemical provides robust protection against tubulo-interstitial and glomerular nephritis, as well as inflammatory infiltration.
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02638948 Completed
Rheumatoid Arthritis
Bristol-Myers Squibb
 February 16 2016 Phase 2
NCT02257151 Completed
Healthy Adult
Bristol-Myers Squibb
 September 2014 Phase 1

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