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INCB086550 selectively inhibited PD-L1 with IC50 of 3.1 nM, 4.9 nM and 1.9 nM for human, rhesus monkey and rat pD-L1, respectively. INCB086550 could not inhibit the binding of PD-L2 to PD-1 at 10 μM. INCB086550 significantly inhibits the PD-1/PD-L1 signaling axis by binding to PD-L1 protein, leading to PD-L1 dimerization and internalization, and has good tumor suppressive effect in a variety of mouse tumor models.
In vitro studies showed that INCB086550 could selectively inhibit PD-L1: the IC50 of INCB086550 on human, rhesus monkey and rat PD-L1 were 3.1 nM, 4.9 nM and 1.9 nM, respectively. INCB086550 could not inhibit the binding of PD-L2 to PD-1 at 10 μM.
INCB086550 could significantly inhibit the binding of PD-1 to human PD-L1 on Chinese hamster ovary (CHO) cells with an IC50 of 13 nM, and the inhibitory effect was more than 90% when INCB086550 concentration exceeded 160 nM.
Flow cytometry and confocal confocal results showed that INCB086550 and PD-L1 monoclonal antibodies (Atezolizumab and Durvalumab) competed to bind to the same site. INCB086550 rapidly induces the dimerization and internalization of PD-L1, and causes its transfer to the nucleus, reducing the level of PD-L1 on the cell surface.
After INCB086550 blocked PD-L1, the ability of PD-1 to recruit protein tyrosine phosphatase (SHP) was decreased, thus enhancing the signal intensity of activated T nuclear factor (NFAT) and promoting the secretion of IFN-γ by immune cells in human peripheral blood.
In vivo antitumor efficacy: On the transplanted tumor model of mouse colon cancer cell line MC38 (expressing human PD-L1), twice daily INCB086550 at 2 mg/kg, 20 mg/kg and 200 mg/kg reduced tumor volume by 32%, 66% and 69%, respectively, on day 16.
Human CD34 positive hematopoietic stem cells were injected into NSG severely combined with immunodeficient mice, and the tumor bearing experiment of breast cancer (MDA-MB-231) was conducted to construct the humanized mouse tumor model. Tumor-bearing mice were given INCB086550 twice daily at 20 mg/kg, 60 mg/kg and 200 mg/kg, and tumor volume decreased by 55%, 54% and 61%, respectively, on day 21. No observable side effects were observed.
| Molecular Weight | 693.79 |
| Formula | C41H39N7O4 |
| CAS Number | 2230911-59-6 |
| Solubility (25°C) | Water ≥ 60 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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