Abstract
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 highest cytotoxicity (EC50 = 1.635 μM). Interestingly, Incyte-001 (injected intravenously 2 mg/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.
Highlights
Immunotherapy is an emerging approach for oncological treatment [1]
Our work shows that Programmed cell death 1 (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
Many studies showed that blockade of the PD-1/PD-L1 interaction could re-activate T cell function such as the secretion of IFN-γ, which suggested the inhibi-tion of immune escape in the tumor cells [24]
Summary
Immunotherapy is an emerging approach for oncological treatment [1]. Especially, the immune checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 pathway get a lot of attention and have shown great improvement in the treatment of several tumors [2,3,4]. The monoclonal antibodies (mAbs) of PD-1/PD-L1 inhibitors have shown significant clinical effectiveness in various tumors including melanoma, lung cancer, Hodgkin lymphoma, urothelial carcinoma, bladder cancer, colorectal cancer, renal cell carcinoma, and glioblastoma [9,10,11,12]. These monoclonal antibodies showing their advantages, have several disadvantages such as lack of oral bioavailability, pro-longed half-life, poor permeability, immune-related adverse effects (irAEs), and relatively lower clinical response in brain tumors [13,14,15]. Using computer-aided drug design (CADD), we analyzed the related amino acid residues that interact with compounds
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
