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| Targets |
Tyrosine kinase 2 (TYK2). BMS-986202 is a selective TYK2 inhibitor that binds to the regulatory pseudokinase domain (JH2) of TYK2. The JH2 domain regulates the catalytic JH1 domain via an allosteric mechanism. By binding to JH2 with high affinity (IC50 = 0.19 nM, Ki = 0.02 nM), BMS-986202 stabilizes the kinase in an inactive conformation, preventing JH1 activation. This allosteric inhibition disrupts TYK2-dependent signaling downstream of cytokine receptors, including Type I interferons (IFNalpha, IFNbeta), IL-6, IL-12, IL-23, and IL-10. BMS-986202 is remarkably selective for TYK2 over other JAK family members (JAK1, JAK2, JAK3) and over 273 other kinases and pseudokinases (>10,000-fold selectivity).
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| ln Vitro |
Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as tracers that influence measurement during the drug development process. It's possible that the pharmacokinetics and functional range of medications contribute to the concern over mutagenesis [1]. Potential benefits of compounds with delayed generation include: (1) compounds with delayed generation may be able to extend the compound's pharmacokinetic characteristics, which could extend the compound's safety, tolerability, and improved tolerance; and (2) compounds with delayed generation may expand intestinal bioavailability. Deuterated compounds may be able to lessen the amount of first-pass metabolism required in the colon and intestinal wall, which would enable a higher percentage of the medicine to reach high bioavailability levels, which dictate its efficacy at low doses and better tolerability. (3) Enhance the properties of metabolism. Drug safety, drug metabolism (4), and hazardous or reactive metabolite reduction are all potential benefits of metabolites. Deuterated chemicals are harmless and have the potential to lessen or completely eradicate the negative effects of medicinal drugs. (5) Preserve medicinal qualities. According to earlier research, deuterated chemicals should maintain comparable biological effects and efficacy to comparable hydrogen molecules.
In cell-free biochemical assays, BMS-986202 binds to the TYK2 JH2 domain with high affinity. The IC50 for TYK2 JH2 binding is 0.19 nM, and the Ki (inhibition constant) is 0.02 nM, as measured in a binding assay using purified TYK2 JH2 domain. The compound has a deuterated structure that reduces metabolic clearance and potentially improves pharmacokinetics. Selectivity is assessed by testing against a panel of over 273 kinases and pseudokinases, showing >10,000-fold selectivity for TYK2 JH2. BMS-986202 is a weak inhibitor of CYP2C19 with an IC50 of 14 uM, but this is unlikely to be clinically relevant at therapeutic concentrations. |
| ln Vivo |
Treatment with BMS-986202 (Compound 7; 3-30 mg/kg; oral; daily; for 9 days) suppresses IL-23-driven acanthosis in mice [1]. Treatment with BMS-986202 (Compound 7; 0.4-10 mg/kg; oral) suppresses IL-12/IL-18-induced IFNγ production in mice. BMS-986202 dose-dependently suppresses IFNγ production by 46% and 80% at dosages of 2 mg/kg and 10 mg/kg, respectively [1]. BMS-986202 (Compound 7; 7-10 mg/kg; oral) is stable in liver microsomes with a half-life of longer than 120 minutes in mice, rats, monkeys, and humans, and a half-life of 89 minutes in dogs. Serum protein binding of BMS-986202 in these species ranges from 89.3% to 96.0%, leaving a good range of useable free fraction of the medication. The oral bioavailability of BMS-986202 is as high as 62-100%[1].
BMS-986202 potently inhibits TYK2-dependent cellular signaling. In IL-23-stimulated human whole blood assays, BMS-986202 inhibits the production of IL-23-induced cytokines (e.g., IL-22, IFNgamma). In cell lines expressing the TYK2 pseudokinase domain, the compound blocks TYK2 autophosphorylation and downstream STAT phosphorylation. The cellular IC50 for inhibition of IL-23 signaling is consistent with the biochemical binding affinity (sub-nanomolar to low nanomolar range). BMS-986202 also inhibits IFNgamma production in a dose-dependent manner, with 46% inhibition at 2 mg/kg and 80% inhibition at 10 mg/kg in an in vivo pharmacodynamic model. The compound shows no significant off-target cellular activity against other JAK family members at concentrations up to 10 uM. |
| Enzyme Assay |
TYK2 JH2 domain binding is assessed using a biochemical binding assay format. Purified TYK2 JH2 domain protein is incubated with a fluorescently labeled tracer that binds to the JH2 binding site. BMS-986202 (0.0001-1000 nM) is added to compete with the tracer. After equilibration, the fluorescence polarization (FP) or time-resolved fluorescence resonance energy transfer (TR-FRET) signal is measured. The IC50 for binding is determined from competition curves, and Ki values are calculated using the Cheng-Prusoff equation. For selectivity profiling, BMS-986202 is tested at 1 uM against a panel of recombinant kinases and pseudokinases using a similar FP or TR-FRET binding platform. Percentage inhibition at 1 uM is calculated, and selectivity is defined as a >10,000-fold difference in binding affinity between TYK2 JH2 and other targets. CYP2C19 inhibition is assessed in human liver microsome assays using CYP-specific substrates (e.g., omeprazole for CYP2C19).
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| Cell Assay |
Cellular potency is measured using IL-23-stimulated human whole blood assays. Healthy donor human blood is collected in sodium heparin tubes. Blood samples are incubated with BMS-986202 at concentrations ranging from 0.001-1000 nM for 1 hour at 37degC, then stimulated with recombinant human IL-23 (10-100 ng/mL) for 18-24 hours. Plasma is separated, and IL-22 or IFNgamma levels are measured by ELISA. IC50 values for inhibition of cytokine production are calculated from dose-response curves. Alternatively, peripheral blood mononuclear cells (PBMCs) isolated from human blood can be used. PBMCs are stimulated with IL-23 in the presence or absence of BMS-986202 for 24-72 hours, and STAT phosphorylation is measured by flow cytometry (p-STAT3, p-STAT4) or Western blot. For other cell types, TYK2-dependent cell lines (e.g., Ba/F3 cells expressing TYK2 mutant) can be used to measure cell proliferation inhibition.
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| Animal Protocol |
Animal/Disease Models: C57BL/6 female mice (9-11 weeks) were injected with IL-23[1].
Doses: 3 mg/kg, 10 mg/kg, 30 mg/kg. Route of Administration: oral administration; injection administration. Daily; lasted 9 days Experimental Results: Suppressed IL-23-induced ear swelling in mice with acanthosis in a dose-response manner. BMS-986202 shows efficacy in various autoimmune mouse models. In an IL-23-driven acanthosis (skin thickening) model, BMS-986202 treatment reduces epidermal thickness and markers of inflammation. In an anti-CD40-induced colitis model, the compound reduces colon inflammation, body weight loss, and disease activity scores. In a spontaneous lupus model, BMS-986202 reduces autoantibody production, proteinuria, and renal pathology. BMS-986202 also inhibits IFNgamma production in a dose-dependent manner in a pharmacodynamic model: 46% inhibition at 2 mg/kg and 80% at 10 mg/kg. In mouse models, the compound is typically administered orally at doses ranging from 1-30 mg/kg once daily for 1-4 weeks depending on the study. Endpoints include histopathological scoring of skin/colon/kidney tissue, cytokine levels in serum (e.g., IL-17, IFNgamma, IL-22), and immune cell infiltration. |
| ADME/Pharmacokinetics |
BMS-986202 is orally active and has a favorable PK profile due to its deuterated structure, which reduces metabolic clearance. In preclinical species, the compound is stable in liver microsomes, with half-lives greater than 120 minutes in mouse, rat, monkey, and human microsomes, and 89 minutes in dog microsomes. The terminal half-life in vivo supports once-daily dosing. The deuterated structure reduces the rate of CYP450-mediated metabolism, particularly at the site of oxidation, leading to increased metabolic stability, reduced clearance, and potentially increased oral bioavailability and longer duration of action. The oral bioavailability in rodents is moderate-to-high. Cmax and AUC are dose-proportional over the tested dose range. Plasma protein binding is high (likely >90%), and distribution volume is moderate. Excretion is primarily via feces and urine.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies demonstrate a favorable safety profile for BMS-986202. At therapeutic doses (e.g., 1-30 mg/kg in mice), the compound is generally well-tolerated with no significant body weight loss or organ toxicity. BMS-986202 is highly selective for TYK2 over other JAK family members (>10,000-fold), which is expected to reduce the class-related adverse events associated with non-selective JAK inhibitors (e.g., thrombosis, anemia, neutropenia, infections). The compound is a weak inhibitor of CYP2C19 (IC50 = 14 uM), which is unlikely to cause significant drug-drug interactions at clinically relevant plasma concentrations. In Phase 1 clinical trials, BMS-986202 demonstrated a favorable safety and tolerability profile, with no serious adverse events reported at the doses tested. Longer-term safety data would be required for approval.
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| References | |
| Additional Infomation |
BMS-986202 is being developed by Bristol-Myers Squibb for the treatment of autoimmune and inflammatory diseases. The compound is an allosteric TYK2 inhibitor that binds to the JH2 pseudokinase domain, providing high selectivity over other JAK family members. This selectivity is designed to avoid the safety liabilities of first-generation JAK inhibitors, including JAK1/2/3 inhibition. BMS-986202 has shown efficacy in preclinical models of psoriasis, inflammatory bowel disease (colitis), and lupus. The compound has a deuterated structure, which may improve metabolic stability and pharmacokinetic properties compared to non-deuterated analogs. Clinical development status: BMS-986202 has entered Phase 1/2 clinical trials for the treatment of autoimmune diseases. The compound is not yet approved for clinical use. The molecular formula is C22H18D3FN6O3, and the molecular weight is 439.46. The CAS number is 1771691-34-9. The compound is also known as BMS986202.
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| Molecular Formula |
C22H21FN6O3
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| Molecular Weight |
439.4574
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| Exact Mass |
439.184
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| CAS # |
1771691-34-9
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| PubChem CID |
155981972
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| Appearance |
White to yellow solid powder
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
32
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| Complexity |
658
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C([H])=NC(C2C([H])=C([H])C([H])=C(C=2OC([H])([H])[H])N([H])C2C(C(N([H])C([2H])([2H])[2H])=O)=C([H])N=C(C=2[H])N([H])C(C2([H])C([H])([H])C2([H])[H])=O)=NC=1[H]
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| InChi Key |
BBRMAVGRWHNAIG-FIBGUPNXSA-N
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| InChi Code |
InChI=1S/C22H21FN6O3/c1-24-22(31)15-11-25-18(29-21(30)12-6-7-12)8-17(15)28-16-5-3-4-14(19(16)32-2)20-26-9-13(23)10-27-20/h3-5,8-12H,6-7H2,1-2H3,(H,24,31)(H2,25,28,29,30)/i1D3
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| Chemical Name |
6-(cyclopropanecarboxamido)-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide
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| Synonyms |
BMS986202 BMS-986202 BMS 986202
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~250 mg/mL (~568.88 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.73 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.73 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2755 mL | 11.3776 mL | 22.7552 mL | |
| 5 mM | 0.4551 mL | 2.2755 mL | 4.5510 mL | |
| 10 mM | 0.2276 mL | 1.1378 mL | 2.2755 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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