April 20, 2024

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The first oral PD-L1 small molecule inhibitor study data released

The first oral PD-L1 small molecule inhibitor study data released


The first oral PD-L1 small molecule inhibitor study data released


In recent years, immune checkpoint inhibitor (ICI) therapy has become the trump card for inhibiting tumor development and prolonging the survival of cancer patients. Representative drugs include ipilimumab targeting CTLA-4, nivolumab and pembrolizumab targeting PD-1, and atezolizumab targeting PD-L1 [1] ].


Although the above-mentioned immune checkpoint inhibitors can activate the body’s immune system, reverse T cell exhaustion, release cytokines and cytotoxic particles, thereby killing tumors, and have been fully verified in clinical treatment; however, there are still 40%-60% of patients do not respond to ICI therapy [2,3].


It is worth noting that the current ICI therapy is mainly based on monoclonal antibody drugs, and its high treatment cost often discourages many patients.

Compared with monoclonal antibodies, in addition to being more convenient for oral administration, small molecule inhibitors also have the advantages of short half-life, simple preparation process, low price, effective penetration of the blood-brain barrier, and easier entry into the tumor microenvironment [4].

Although previous studies have found that some small molecules can block the binding of PD-1 and PD-L1, they do not have good druggability [5].

Recently, Jonathan Rios-Doria and his team from Incyte Corporation in the United States published important research results in the famous journal Cancer Discovery .

They found that INCB086550, a small molecule inhibitor targeting PD-L1, can block PD-L1-mediated inhibition. Signals, activate immune cells, and enhance the immune system’s immune surveillance function on tumors [5].

Their research results provide another means for PD-L1-based tumor immunotherapy, enriching ICI treatment methods and bringing new hope to tumor patients.


The first oral PD-L1 small molecule inhibitor study data released


Next, let’s take a look at the drug characteristics and early clinical manifestations of the oral PD-L1 inhibitor INCB086550.


Through medicinal chemistry and other means, the Jonathan Rios-Doria team found that INCB086550 can bind to PD-L1 protein in human, macaque and rat. Meanwhile, the half maximal inhibitory concentrations (IC50) of INCB086550 on human, rhesus monkey and rat PD-L1 were 3.1 nM, 4.9 nM and 1.9 nM, respectively.

In contrast, INCB086550 also failed to inhibit the binding of PD-L2 to PD-1 when the concentration reached 10 μM . The above results indicate that the inhibitory effect of INCB086550 on PD-L1 is selective .


Cytological experiments further confirmed that INCB086550 can significantly inhibit the binding of PD-1 to human PD-L1 on Chinese hamster ovary cells (CHO) with IC50 of 13 nM, and when the concentration of INCB086550 exceeds 160 nM, the inhibitory effect exceeds 90% .


Experiments such as flow cytometry and confocal fluorescence microscopy showed that INCB086550 and PD-L1 monoclonal antibody compete for binding to the same site . Vituzumab, durvalumab) cannot bind to PD-L1 molecules on CHO cells.

Live-cell microscopic imaging further confirmed that INCB086550 rapidly induced the dimerization and internalization of PD-L1, and translocated it into the nucleus, reducing the level of PD-L1 on the cell surface .


The first oral PD-L1 small molecule inhibitor study data released

Small molecule compound INCB086550 inhibits PD-L1 expression and promotes its internalization


Interestingly, the Rios-Doria team found that the higher the level of PD-L1 on the tumor cell surface, the lower the IC50 of INCB086550.

They believe that the reason behind this may be that the high density of PD-L1 is more convenient for dimerization, which promotes its internalization, resulting in a greater decrease in surface PD-L1 levels.


This result also suggests that the treatment effect of INCB086550 may be more ideal for tumor types with high PD-L1 expression . Although INCB086550 is stronger when it is strong, its inhibitory effect is not long-term.

The Rios-Doria team found that after stopping the use of INCB086550, PD-L1 levels on human breast cancer cells (MDA-MB-231) recovered rapidly .

As for the mechanism of action of INCB086550, the Rios-Doria team found that after INCB086550 blocked PD-L1, the PD-1/PD-L1 pathway was blocked, resulting in a decrease in the ability of PD-1 to recruit protein tyrosine phosphatase (SHP), thereby enhancing the Activated T-cell nuclear factor (NFAT) signal intensity promotes the secretion of IFN-γ by immune cells in human peripheral blood , achieving a similar effect to atezolizumab.


The first oral PD-L1 small molecule inhibitor study data released

INCB086550 significantly inhibits tumorigenesis and progression


In order to further understand the inhibitory effect of INCB086550 on PD-L1 in vivo and its distribution in the tumor microenvironment, the Rios-Doria team used tumor-bearing mice to conduct in vivo pharmacokinetic and pharmacodynamic studies.

It was found that after a single 15 mg/kg administration of INCB086550 within 24 hours, PD-L1 levels on tumor cells of MDA-MB-231 tumor-bearing mice decreased by 26%.

The inhibitory effect on PD-L1 gradually increased with the increase of the dosage and the number of administrations.

After two doses of INCB086550 at 200 mg/kg within 24 hours, the PD-L1 level decreased by as much as 91%. .


In addition, in this model, the Rios-Doria team also found that 30 minutes after a single dose of 150 mg/kg INCB086550, the inhibitory effect on cell surface PD-L1 was more than 50%, and 24 hours later, PD-L1 was inhibited. -L1 suppression effect increased to 78%.

And with the prolongation of administration time, the drug concentration of INCB086550 in tumor gradually increased, while the drug concentration in serum decreased gradually .


Happily, the Rios-Doria team also detected the presence of INCB086550 in PD-L1-negative tumors (HT-29, a human colon cancer cell line) , suggesting that its infiltration does not depend on binding to PD-L1.

In addition, they also found that the concentration of INCB086550 in tumor tissue was significantly higher than that in peripheral blood, indicating that it has better tumor penetration and retention capacity. This is also the key to the attractiveness of INCB086550 treatment compared to monoclonal antibodies.


In order to understand the anti-tumor effect of INCB086550, the Rios-Doria team expressed the human PD-L1 protein on the mouse colon cancer cell line MC38, and carried out tumor-bearing experiments on C57BL/6 mice.

The results showed that after twice daily administration of INCB086550 at 2 mg/kg, 20 mg/kg and 200 mg/kg in tumor-bearing mice, the tumor volume decreased by 32%, 66% and 69%, respectively, on day 16 .

Notably, atezolizumab at 5 mg/kg had a 73% tumor-inhibitory effect, comparable to INCB086550. Meanwhile, the infiltration level of CD8+ T cells in the tumor microenvironment was significantly increased after INCB086550 treatment .


In addition, they also injected human CD34-positive hematopoietic stem cells into NSG severe combined immunodeficiency mice, and carried out breast cancer (MDA-MB-231) tumor-bearing experiments to construct a humanized mouse tumor model.

Consistent with the previous results, tumor-bearing mice treated with INCB086550 at 20 mg/kg, 60 mg/kg, and 200 mg/kg twice daily had tumor volumes decreased by 55%, 54%, and 61% on day 21, respectively. % , achieved a similar anti-tumor effect as atezolizumab, which depends on a healthy immune system.


RNA-seq results also showed that the expression levels of genes such as IFN-γ, PD-1, LAG3, and Granzyme B in MDA-MB-231 tumor tissues after INCB086550 treatment were significantly increased , suggesting that T cells were in an activated state. Importantly, the small molecule treatment did not cause visible side effects.


The above preclinical data indicate that INCB086550 binds to PD-L1 protein, leading to its dimerization and further internalization into the nucleus.

Because the level of PD-L1 on the cell surface is significantly reduced, INCB086550 treatment can block immunosuppressive signals, activate the immune system, enhance the effector function of immune cells and local infiltration of tumors, thereby exerting tumor immune surveillance functions and controlling tumor occurrence and development.


To understand the clinical effect of INCB086550, the Rios-Doria team conducted a Phase 1 clinical study. This clinical study is still in progress.


The first oral PD-L1 small molecule inhibitor study data released

INCB086550 demonstrated strong tumor inhibition in Phase 1 clinical trials


From the early data of the Phase 1 clinical study, INCB086550 treatment can significantly inhibit the level of PD-L1 on monocytes in a dose-dependent manner. At the same time, INCB086550 treatment can increase the serum CXCL9 by 1.8 times, CXCL10 by 1.4 times, and IFN-γ by 3.8 times .


The above results indicate that the immune system is activated after INCB086550 treatment. The results of the Olink® proteomic assay showed that serum levels of other IFN-γ-related cytokines and immunomodulatory proteins, including factors such as Granzyme B and Granzyme H, were also increased. Excitingly, a 54-year-old female patient shrank significantly after the treatment.


All in all, the authors found and confirmed that the small molecule compound INCB086550 can significantly inhibit the PD-1/PD-L1 signaling axis, leading to the dimerization and internalization of PD-L1, thereby enhancing the body’s T cell immune response, exerting a strong anti-tumor immune function , and promoting It has shown great therapeutic potential and application value in a variety of mouse tumor models and human clinical trials.


Due to the poor specificity of small molecule drugs and the possible existence of multiple targets, more extensive and in-depth studies on the side effects of INCB086550 should be carried out in the future.

However, considering the advantages of low production cost of small molecule drugs, easy tumor penetration, and oral administration, INCB086550 is more convenient for combination therapy and promotion.

We expect that INCB086550 will maintain a high therapeutic effect in subsequent clinical trials, and provide an economical, practical and safe anticancer drug for the majority of cancer patients.








[1] Im K, Combes AJ, Spitzer MH, Satpathy AT, Krummel MF. Archetypes of checkpoint-responsive immunity. Trends Immunol. 2021;42(11):960-974.

[2] Kalaora S, Nagler A, Wargo JA, Samuels Y. Mechanisms of immune activation and regulation: lessons from melanoma. Nat Rev Cancer. 2022;10.1038/s41568-022-00442-9.

[3] Huang AC, Zappasodi R. A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance. Nat Immunol. 2022;10.1038/s41590-022-01141-1.

[4] Imai K, Takaoka A. Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer. 2006;6(9):714-727.

[5] Guzik K, Tomala M, Muszak D, et al. Development of the Inhibitors that Target the PD-1/PD-L1 Interaction-A Brief Look at Progress on Small Molecules, Peptides and Macrocycles. Molecules. 2019;24(11):2071. Published 2019 May 30.

[6] Koblish HK, Wu L, Wang LS, et al. Characterization of INCB086550, a potent and novel small-molecule PD-L1 inhibitor. Cancer Discov. 2022;candisc.1156.2021.

The first oral PD-L1 small molecule inhibitor study data released

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