INCB086550

Biological Activity

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.

Chemical Information

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

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Holly K Koblish , et al. Characterization of INCB086550, a potent and novel small-molecule PD-L1 inhibitor

[2] Holly K Koblish, et al. Cancer Discov. Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor