Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency
Abstract
:1. Introduction
2. Results
2.1. Selection of Virtual Hit Compounds
2.2. Identification of VIS310 as Hit Compound
2.3. VIS310 Analogues and Structure–Activity Relationships
2.4. pKa Measurements
2.5. Binding Modes of VIS310 Analogues to PD-L1
2.6. Ligand Binding Displacement Assay of PD-1/PD-L1 Complex
3. Discussion
4. Materials and Methods
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Virtual Hits | GScore (kcal/mol) | Binder [a] | Kd ± c.v. [b] (μM) | MW (Dalton) | BEI |
---|---|---|---|---|---|
BMS-202 (5) | −10.22 | x | 8.13 ± 1.38 | 419 | 12.1 |
VIS284 (6) | −7.94 | x | >250 | 192 | n.d. [c] |
VIS285 (7) | −7.05 | x/o | >250 | 175 | n.d. |
VIS303 (8) | −9.13 | x | >250 | 299 | n.d. |
VIS310 (9) | −7.22 | x | 163.75 ± 33.61 | 180 | 21.0 |
VIS545 (10) | −9.09 | x/o | >250 | 269 | n.d. |
VIS826 (11) | −6.05 | x | >250 | 316 | n.d. |
VIS877 (12) | −4.76 | x | >250 | 226 | n.d. |
VIS879 (13) | −4.56 | x | >250 | 254 | n.d. |
VIS1079 (14) | −7.61 | x/o | >250 | 209 | n.d. |
VIS32926 (15) | −7.71 | x/o | >250 | 195 | n.d. |
Virtual Hits | pH 7.2 Kd ± c.v. [a] (μM) | pH 6.2 Kd ± c.v. [a] (μM) | MW (Dalton) | BEI (pH 6.2) |
---|---|---|---|---|
BMS-202 (5) | 8.13 ± 1.38 | 4.50 ± 0.56 | 419 | 12.8 |
VIS310 (9) | 164 ± 33.6 | 47.8 ± 11.5 | 180 | 24.0 |
VIS1200 (16) | >1000 | 95.6 ± 20.6 | 164 | 24.5 |
VIS1201 (17) | >1000 | 45.2 ± 10.6 | 152 | 28.6 |
VIS1202 (18) | >1000 | 55.4 ± 9.86 | 166 | 25.6 |
VIS1203 (19) | >1000 | 54.9 ± 8.20 | 166 | 25.7 |
VIS1204 (20) | 148 ± 71.3 | 70.8 ± 12.7 | 212 | 19.6 |
Compounds | pKa1 | pKa2 | pKa3 |
---|---|---|---|
BMS-202 (5) | n.d. [a] | 8.39 ± 0.05 [c] | - |
VIS310 (9) | 5.65 ± 0.01 [b] | 9.32 ± 0.02 [d] | n.d. [e] |
VIS1200 (16) | 5.26 ± 0.01 [b] | - | n.d. [e] |
VIS1201 (17) | 5.35 ± 0.12 [b] | 8.64 ± 0.01 [d] | n.d. [e] |
VIS1202 (18) | 5.38 ± 0.01 [b] | 8.97 ± 0.03 [d] | n.d. [e] |
VIS1203 (19) | 5.38 ± 0.01 [b] | 9.17 ± 0.02 [d] | n.d. [e] |
VIS1204 (20) | 5.30 ± 0.01 [b] | - | n.d. [e] |
Vehicle Kd ± c.v. [a] (pH 6.2) | VIS1201 (50 μM) Kd ± c.v. [a] (pH 6.2) | VIS1201 (100 μM) Kd ± c.v. [a] (pH 6.2) | |
---|---|---|---|
PD-1/PD-L1 | 2.50 ± 0.50 | 9.68 ± 2.57 | >30 |
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Bianconi, E.; Riccio, A.; Ruta, L.; Bigiotti, C.; Carotti, A.; Moretti, S.; Cerra, B.; Gioiello, A.; Ferlin, S.; Puxeddu, E.; et al. Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency. Int. J. Mol. Sci. 2023, 24, 5535. https://doi.org/10.3390/ijms24065535
Bianconi E, Riccio A, Ruta L, Bigiotti C, Carotti A, Moretti S, Cerra B, Gioiello A, Ferlin S, Puxeddu E, et al. Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency. International Journal of Molecular Sciences. 2023; 24(6):5535. https://doi.org/10.3390/ijms24065535
Chicago/Turabian StyleBianconi, Elisa, Alessandra Riccio, Luana Ruta, Carlo Bigiotti, Andrea Carotti, Sonia Moretti, Bruno Cerra, Antimo Gioiello, Simone Ferlin, Efisio Puxeddu, and et al. 2023. "Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency" International Journal of Molecular Sciences 24, no. 6: 5535. https://doi.org/10.3390/ijms24065535