This preprint is under consideration at Medicinal Chemistry Research. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
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Research Article
Mei Liu
Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College
Corresponding Author
ORCiD: https://orcid.org/0000-0003-0540-7566
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have become a "game-changer" in the cancer treatment. However, none of the small molecular inhibitors has been approved yet. To explore the advantages and disadvantages of various scaffolds, different biological evaluations were performed on the three selected small inhibitors, namely Incyte-001, Incyte-011, and BMS-1001. In the HTRF assay, BMS-1001 showed the best binding activity for PD-L1 (IC50 = 0.9 nM) while Incyte-011 (IC50 = 5.293 nM) was twice more potent than the Incyte-001 (IC50 = 11 nM). Also, only Incyte-011 increased the IFN-γ production. Notably, the Incyte-001 exhibited the high-est cytotoxicity (EC50 = 1.635 μM). Interestingly, Incyte-001 (injected intravenously 2mg/kg) also displayed good blood-brain barrier permeability and reached a high concentration in the brain tissue. Finally, molecular docking and modeling studies suggested that the compounds bind in a pocket at the interface of two PD-L1 monomers. Overall, our work shows that PD-1/PD-L1 small molecular inhibitors have different biological characteristics depending on their unique skeletons, which can be further improved to better their clinical application.
Keywords
Cancer immunotherapy, PD-1/PD-L1, Small molecule inhibitors, Immune checkpoint inhibitors
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This is a list of supplementary files associated with this preprint. Click to download.
- scheme1.jpg
Structures of Incyte-001, Incyte-011 and BMS-1001
- scheme2.jpg
Reagents and conditions: (a) phenylboronic acid, Pd(PPh3)4, Na2CO3, 1,4-dioxane, H2O; (b) HATU, DIPEA, DMF; (c) pinacol vinylboronate, Pd(dppf)Cl2, NaHCO3, 1,4-dioxane, H2O; (e) NaIO4, K2OsO4, 2,6-lutidine, THF, H2O; (f) ethanolamine, NaBH3CN, DCM
- scheme3.jpg
Reagents and conditions: (a) Bis(pinacolato)diboron, Pd(dppf)Cl2, KOAc, 1,4-dioxane; (b) Pd(PPh3)4, Na2CO3, 1,4-dioxane, H2O; (c) HATU, DIPEA, DMF; (d) pinacol vinylboronate, Pd(PPh3)4, Na2CO3, 1,4-dioxane, H2O; (e) NaIO4, K2OsO4, 2,6-lutidine,THF, H2O; (f) ethanolamine, NaBH3CN, DMF
- scheme4.jpg
Reagents and conditions: (a) BH3-THF, THF; (b) XPhos Pd G2, K3PO4, THF; (c) DIAD, PPh3, THF; (d) Cs2CO3, DMF; (e) NaBH3CN, HAc, DMF
- Graphicsabstract.jpg
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CURRENT STATUS: Under Review
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This preprint is under consideration at Medicinal Chemistry Research. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Mei Liu
Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College
Corresponding Author
ORCiD: https://orcid.org/0000-0003-0540-7566
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 19 Feb, 2021
No community comments so far
Editorial decision: Major Revision
On 09 Mar, 2021
Reviews received
Received 10 Feb, 2021
Reviewers invited
Invitations sent on 10 Feb, 2021
Editor assigned
On 07 Feb, 2021
First submitted
On 04 Feb, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have become a "game-changer" in the cancer treatment. However, none of the small molecular inhibitors has been approved yet. To explore the advantages and disadvantages of various scaffolds, different biological evaluations were performed on the three selected small inhibitors, namely Incyte-001, Incyte-011, and BMS-1001. In the HTRF assay, BMS-1001 showed the best binding activity for PD-L1 (IC50 = 0.9 nM) while Incyte-011 (IC50 = 5.293 nM) was twice more potent than the Incyte-001 (IC50 = 11 nM). Also, only Incyte-011 increased the IFN-γ production. Notably, the Incyte-001 exhibited the high-est cytotoxicity (EC50 = 1.635 μM). Interestingly, Incyte-001 (injected intravenously 2mg/kg) also displayed good blood-brain barrier permeability and reached a high concentration in the brain tissue. Finally, molecular docking and modeling studies suggested that the compounds bind in a pocket at the interface of two PD-L1 monomers. Overall, our work shows that PD-1/PD-L1 small molecular inhibitors have different biological characteristics depending on their unique skeletons, which can be further improved to better their clinical application.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
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