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INCB-086550 (INCB-086550) is a novel, investigational and selective small molecule PD-1/PD-L1 inhibitor based on the biphenyl scaffold core structure first disclosed by BMS company. It acts by blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity.
| Targets |
For pleural effusion cells, INCB086550 (0.1–10,000 nM, 20 hours) has no discernible toxicity [1]. PD-L1 on the cell surface dimerizes when exposed to NCB086550 (1 µmol/L) for 24 hours, which causes internalization [1].
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| ln Vitro |
For pleural effusion cells, INCB086550 (0.1–10,000 nM, 20 hours) has no discernible toxicity [1]. PD-L1 on the cell surface dimerizes when exposed to NCB086550 (1 µmol/L) for 24 hours, which causes internalization [1].
INCB086550 selectively blocks PD-1 binding to PD-L1 on CHO cells expressing human PD-L1, with an IC₅₀ of 13.2 nmol/L. It competes with clinical anti-PD-L1 monoclonal antibodies (atezolizumab, durvalumab) for overlapping binding sites on PD-L1. Induces PD-L1 dimerization as shown by SEC-MALS and ITC. Induces PD-L1 internalization in CHO PD-L1 cells, with maximal internalization ~4 hours post-treatment. Reduces unoccupied cell-surface PD-L1 in a concentration-dependent manner, with EC₅₀ values inversely correlating with PD-L1 expression levels (e.g., 0.1 nmol/L in high-expressing MBT2 cells). Abolishes PD-1–mediated SHP recruitment (IC₅₀ = 6.3 nmol/L) and enhances NFAT signaling (EC₅₀ = 21.4 nmol/L). Stimulates IFNγ production in primary human T cells (EC₅₀ = 9.8 nmol/L) and in SEB-stimulated whole blood assays. No overt cytotoxicity observed in vitro. |
| ln Vivo |
In the MDA-MB-231 mouse model, INCB086550 (15, 200 mg/kg, active region, once or twice) suppresses over 90% of occupied cell surface PD-L1 [1]. The MC38 huPD-L1 tumor model is inhibited in its growth by INCB086550 (2, 20, or 200 mg/kg, twice daily in mouse model) [1].
INCB086550 reduces tumor growth in humanized mouse models expressing human PD-L1. In MC38-huPD-L1 tumor-bearing immunocompetent mice, oral dosing (2, 20, 200 mg/kg BID) resulted in tumor growth inhibition of 32%, 66%, and 69%, respectively, comparable to atezolizumab. Activity is immune-mediated, as no efficacy was observed in immunodeficient mice. In CD34⁺ humanized mice bearing MDA-MB-231 tumors, INCB086550 (20, 60, 200 mg/kg BID) showed tumor growth inhibition of 55%, 54%, and 61%, similar to atezolizumab. Increases intratumoral CD8⁺ T-cell infiltration and upregulates T-cell activation gene signatures (e.g., Ifng, Pdcd1, Lag3, Gzmb). Reduces unoccupied cell-surface PD-L1 in tumors in a dose- and time-dependent manner. Shows high tumor-to-plasma ratio (5- to 10-fold) and penetrates PD-L1-negative tumors. Well tolerated in mice up to 200 mg/kg BID. |
| Enzyme Assay |
A homogeneous time-resolved fluorescence (HTRF) assay was used to measure binding of INCB086550 to recombinant PD-L1 from human, cynomolgus, rat, and mouse sources. Proteins were incubated with the compound for 40 minutes, followed by addition of Europium cryptate-labeled anti-human IgG and anti-His allophycocyanin. Fluorescence ratio was measured to determine IC₅₀ values.
Size-exclusion chromatography with multi-angle light scattering (SEC-MALS) was performed to assess molecular weight of PD-L1 in complex with INCB086550, revealing dimer formation. Isothermal titration calorimetry (ITC) was used to confirm binding stoichiometry and dimerization. Surface plasmon resonance (SPR) was used to demonstrate competition between INCB086550 and anti-PD-L1 antibodies (atezolizumab, durvalumab) for PD-L1 binding. |
| Cell Assay |
Cell viability assay [1]
Cell Types: pleural effusion cells Tested Concentrations: 0.1-10000 nM Incubation Duration: 20 hrs (hours) Experimental Results: No obvious toxicity to pleural effusion cells. Immunofluorescence[1] Cell Types: CHO PD-L1 Cell Tested Concentrations: 1 µmol/L Incubation Duration: 24 hrs (hours) Experimental Results: Overall PD-L1 reduction in CHO PD-L1 cells. Demonstrates rapid internalization of PD-L1, reaching maximum in approximately 4 hrs (hours). CHO cells expressing human PD-L1 were treated with INCB086550 and stained with PE-labeled PD-1 to measure inhibition of binding via high-content imaging. Flow cytometry was used to assess competition with anti-PD-L1 antibodies (clones MIH1 and 28-8) on CHO PD-L1 and MDA-MB-231 cells. Confocal microscopy and live-cell imaging were performed to visualize PD-L1 internalization and colocalization with Golgi markers after INCB086550 treatment. A PD-1–SHP reporter assay in U2OS/PD-L1 and Jurkat-PD-1-SHP cells was used to measure inhibition of PD-1 signaling. An NFAT reporter assay in PD-L1-expressing CHO cells and Jurkat-PD-1-NFAT cells was used to assess T-cell signaling activation. Cytokine secretion (IFNγ) was measured in primary human T cells co-cultured with CHO PD-L1 cells and in SEB-stimulated whole blood using Luminex or ELISA. |
| Animal Protocol |
Animal/Disease Models: Mice bearing MDA-MB-231 xenografts [1]
Doses: 15, 200 mg/kg Route of Administration: po (oral gavage) Experimental Results: MDA-MB-231 unoccupied tumors after 24 hrs (hrs (hours)) Cell surface PD-L1 is diminished. Animal/Disease Models: C57BL/6 and NSG mice with established MC38-huPD-L1 tumors [1] Doses: 2, 20 or 200 mg/kg Route of Administration: po (oral gavage) Experimental Results: Induction of PD- L1 dose-dependent reduction was achieved using the antibody clone MIH1 that binds to PD-1. At the 200 mg/kg dose, cell surface occupied by PD-L1 was diminished by >90%. For pharmacokinetic/pharmacodynamic studies, BALB/c nu/nu mice bearing MDA-MB-231 xenografts were dosed orally with INCB086550 (15 or 200 mg/kg once or twice daily). Tumors and plasma were collected at 24 hours for flow cytometry and HPLC analysis. For efficacy studies in MC38-huPD-L1 tumors, C57BL/6 or NSG mice were inoculated subcutaneously and dosed orally with INCB086550 (2, 20, 200 mg/kg BID) or atezolizumab (5 mg/kg IP every 5 days). Tumor volumes were measured regularly. For humanized mouse studies, CD34⁺-engrafted NSG mice bearing MDA-MB-231 tumors were dosed orally with INCB086550 (20, 60, 200 mg/kg BID) or atezolizumab (5 mg/kg twice weekly). Compound was formulated in 5% dimethylacetamide in 0.5% methylcellulose for oral gavage. |
| ADME/Pharmacokinetics |
INCB086550 showed high tumor penetration in xenograft models, with a tumor-to-plasma AUC ratio of 5–10. In MDA-MB-231 tumor-bearing mice, tumor concentrations exceeded whole blood IC₅₀ for more than 24 hours after twice-daily administration. Within 30 minutes of administration, unbound PD-L1 on tumor cells rapidly decreased, and the inhibitory effect lasted for up to 24 hours. In a Phase I clinical study, a dose-dependent reduction of free PD-L1 on monocytes was observed, with the strongest inhibitory effect observed at 200 mg twice daily.
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| Toxicity/Toxicokinetics |
In a 28-day rat toxicology study, INCB086550 was well tolerated at doses up to 1000 mg/kg/day. Only at the highest dose was a slight decrease in erythrocyte parameters and minimal intestinal tissue cell infiltration observed. In monkeys, vomiting was observed at doses ≥200 mg/kg/day, but no target organ toxicity was observed. In mice, no adverse reactions were observed at effective doses (up to 200 mg/kg twice daily).
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| References | |
| Additional Infomation |
The PD-L1 inhibitor INCB086550 is an orally administered small molecule inhibitor that inhibits the immunosuppressive ligand programmed death-ligand 1 (PD-L1; differentiation cluster 274; CD274), possessing potential immune checkpoint inhibitory and antitumor activity. After administration, INCB086550 specifically targets PD-L1 expressed on the surface of tumor cells, preventing its binding and activation to the receptor programmed death receptor 1 (PD-1; PDCD1; CD279; programmed death-1). This reverses T cell inactivation induced by the PD-L1/PD-1 signaling pathway, promotes T cell proliferation, and enhances cytotoxic T lymphocyte (CTL)-mediated antitumor immune responses against PD-L1-expressing tumor cells. PD-L1 is a transmembrane protein expressed on activated T cells, overexpressed in certain cancer types, and plays a crucial role in tumor cell immune escape.
INCB086550 is an orally administered small molecule PD-L1 inhibitor that induces PD-L1 dimerization and internalization, with a mechanism of action different from monoclonal antibodies. In preclinical models, INCB086550 demonstrated immune activation and antitumor efficacy comparable to anti-PD-L1 antibodies. Preliminary data from a Phase I clinical trial showed that INCB086550 dose-dependently activated PD-L1 and increased plasma levels of CXCL9, CXCL10, IFNγ, and soluble PD-L1, while tumor shrinkage was observed in one patient. INCB086550 holds promise as an alternative to antibody-based immune checkpoint inhibitors, offering potential advantages in tissue penetration and the convenience of oral administration. |
| Molecular Formula |
C41H39N7O4
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|---|---|
| Molecular Weight |
693.808
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| Exact Mass |
693.31
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| Elemental Analysis |
C, 70.98; H, 5.67; N, 14.13; O, 9.22
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| CAS # |
2230911-59-6
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| PubChem CID |
135146787
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.42±0.1 g/cm3(Predicted)
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| Boiling Point |
859.8±65.0 °C(Predicted)
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
52
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| Complexity |
1280
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O([H])[C@]1([H])C([H])([H])C([H])([H])N(C([H])([H])C2=C([H])N=C3C(=NC([H])=C([H])C3=C2[H])N([H])C2=C([H])C([H])=C([H])C(=C2C([H])([H])[H])C2C([H])=C([H])C([H])=C(C=2C([H])([H])[H])C2=NC3C(=C(C#N)C([H])=C(C=3[H])C([H])([H])N3C([H])([H])C([H])([H])[C@@]([H])(C(=O)O[H])C3([H])[H])O2)C1([H])[H]
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| InChi Key |
QARLNMDDSQMINK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C41H39N7O4/c1-24-32(5-3-7-34(24)40-46-36-17-26(15-30(18-42)38(36)52-40)20-47-13-10-29(22-47)41(50)51)33-6-4-8-35(25(33)2)45-39-37-28(9-12-43-39)16-27(19-44-37)21-48-14-11-31(49)23-48/h3-9,12,15-17,19,29,31,49H,10-11,13-14,20-23H2,1-2H3,(H,43,45)(H,50,51)
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| Chemical Name |
1-((7-cyano-2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid
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| Synonyms |
INCB 086550; PD-1/PD-L1-IN-8; PD-1; INCB-86550; INCB86550; PD-L1-IN-8;INCB-086550;INCB086550; INCB 86550;
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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) |
H2O : ~83.33 mg/mL (~120.11 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4413 mL | 7.2066 mL | 14.4132 mL | |
| 5 mM | 0.2883 mL | 1.4413 mL | 2.8826 mL | |
| 10 mM | 0.1441 mL | 0.7207 mL | 1.4413 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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