A Comparative Study of the Recent Most Potent Small-Molecule PD-L1 Inhibitors: What Can We Learn?
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.
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Structures of Incyte-001, Incyte-011 and BMS-1001
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
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
Reagents and conditions: (a) BH3-THF, THF; (b) XPhos Pd G2, K3PO4, THF; (c) DIAD, PPh3, THF; (d) Cs2CO3, DMF; (e) NaBH3CN, HAc, DMF
Posted 19 Feb, 2021
Received 10 Feb, 2021
Invitations sent on 10 Feb, 2021
On 07 Feb, 2021
On 04 Feb, 2021
A Comparative Study of the Recent Most Potent Small-Molecule PD-L1 Inhibitors: What Can We Learn?
Posted 19 Feb, 2021
Received 10 Feb, 2021
Invitations sent on 10 Feb, 2021
On 07 Feb, 2021
On 04 Feb, 2021
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