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. 2024 Mar 15;15(4):518–523. doi: 10.1021/acsmedchemlett.4c00014

Design, Synthesis, and Evaluation of 8-(o-Tolyl)quinazoline Derivatives as Small-Molecule PD-1/PD-L1 Antagonists

Xingye Wu †, He Li †, Han Liu †, Xueyan Ding †, Xinting Chen †, Chenxi Yin †, Yali Gao ‡,*, Junjie Ma †,*
PMCID: PMC11017391  PMID: 38628793

Abstract

graphic file with name ml4c00014_0007.jpg

Small-molecule inhibitors targeting programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions can compensate for the shortcomings of antibody-based inhibitors and have attracted considerable attention, some of which have already entered clinical trials. Herein, based on our previous study on small-molecule PD-L1 inhibitors, we reported a series of 8-(o-tolyl)quinazoline derivatives by the skeleton merging strategy. Homogenous time-resolved fluorescence (HTRF) assay against PD-1/PD-L1 interaction identified compound A5, which showed the most potent inhibition with an IC50 value of 23.78 nM. Meanwhile, based on the results of HTRF assay, the structure–activity relationships (SARs) of the tail were focused on. Cell-based PD-1/PD-L1 blockade assay further revealed that A5 significantly blocked the PD-1/PD-L1 interaction at 1.1 μM in the co-culture system of Jurkat-NFAT-PD-1 cells and Hep3B-OS8-hPD-L1 cells with no significant cytotoxicity on Jurkat cells. Moreover, the proposed binding mode of A5 was investigated by a docking analysis. These results indicate that compound A5 is a promising lead compound that deserves further investigation.

Keywords: Tumor immunotherapy, PD-1/PD-L1, Small-molecule inhibitors, 8-(o-Tolyl)quinazoline

Tumor immunotherapy, as another important antitumor therapeutic method after traditional chemotherapy and targeted therapy, involves restoring the body’s normal antitumor immune response to control and eliminate tumors. In recent years, tumor immunotherapy has been regarded as a new hope for conquering tumors.1,2 Among them, immune checkpoint inhibitors blocking the PD-1/PD-L1 interaction have achieved tremendous success.3−8 To date, several monoclonal antibodies (mAbs) that bind PD-1 or PD-L1 to block PD-1/PD-L1 interaction have been approved for the treatment of multiple types of cancers, including nivolumab, pembrolizumab, cemiplimab, camrelizumab, atezolizumab, avelumab, durvalumab, etc.9−12 Although mAbs show good clinical efficiency, durable response, and prolonged survival, their inherent shortcomings still limit the widespread use in the clinic, such as high cost, lack of oral bioavailability, poor permeability, and immune-related adverse events.13 Compared to therapeutic mAbs, small molecule drugs have better penetration, controlled pharmacokinetics, better oral bioavailability, and reasonable half-life due to their low molecular weights. Thus, development of small molecule inhibitors targeting PD-1/PD-L1 interaction exhibits great promise.14,15 In recent years, great advances have been made in the field of small molecule PD-1/PD-L1 inhibitors. Among them, biphenyl PD-L1 inhibitors that block the PD-1/PD-L1 interaction by binding to PD-L1 have gained more attention due to their outstanding inhibitory activity and clear mechanism of action.16−21 Since the disclosure of a series of biphenyl compounds (e.g., BMS-37, BMS-202, and BMS-1166, Figure 1) as PD-L1 inhibitors by Bristol Myers Squibb (BMS) in 2015, numerous biphenyl-based PD-L1 inhibitors have been reported.22 Notably, IMMH-010 (Phase I, Figure 1) developed by Chasesun and MAX-10181 (Phase I, Figure 1) developed by Maxinovel are currently undergoing clinical trials.23,24 In the continuing research, based on the characteristics of the binding pocket of the dimerized PD-L1 with inhibitors, a class of symmetrical biphenyl PD-L1 inhibitors were reported,25,26 such as LH130 (Figure 1) designed by Hu’s group and INCB086550 (Phase II, Figure 1) disclosed by Incyte,27,28 which could occupy a larger space in the binding pocket and also exhibited outstanding inhibition on the PD-1/PD-L1 interaction.

Figure 1.

Figure 1

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Chemical structures of representative biphenyl PD-L1 inhibitors.

In our previous study, we reported a series of PD-L1 inhibitors with 8-phenylquinazoline as the core skeleton (6) by performing a ring-fusion strategy at the 2- and 3-positions of the biphenyl structure.29 Molecular docking analysis showed that the fused pyrimidine moiety in the core skeleton provided additional π-alkyl interactions with Ala121 and Met115 of PD-L1, enhancing the binding of the compound to PD-L1. In this study, given the characteristics of the binding pocket of dimerized PD-L1 with inhibitors and the design of symmetrical PD-L1 inhibitors, we designed a novel series of 8-(o-tolyl)quinazoline derivatives by merging the core skeleton of 8-phenylquinazoline PD-L1 inhibitors with that of reported biphenyl PD-L1 inhibitors, and the SARs of the tail were focused on (Figure 2).

Figure 2.

Figure 2

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Design strategy of target compounds.

The synthesis of target compounds A1–A20 is illustrated in Scheme 1. The intermediates i-1–i-4 were prepared based on our previously reported method.28 The intermediate i-5 was synthesized by the chlorination reaction of commercially available (3-bromo-2-methylphenyl)methanol and SOCl2, and i-5 further reacted with 2,4-dihydroxy-5-chlorobenzaldehyde via a selective nucleophilic substitution reaction to produce intermediate i-6. Intermediate i-7 was synthesized by the Miyaura borylation reaction of intermediate i-6 and bis(pinacolato)diboron using PdCl2(PPh3)2 as a catalyst. i-7 further reacted with 3-(bromomethyl)benzonitrile to obtain intermediate i-8. The key intermediate i-9 was synthesized through a Suzuki–Miyaura coupling reaction of i-4 and i-8 employing XPhos Pd G2 as a catalyst. Finally, target compounds A1–A20 were obtained through a Borch reductive amination reaction of i-9 with appropriate amines using NaBH(OAc)3, NaBH3CN, or NaBH4 as a reductant.

Scheme 1. Reagent and Conditions.

Scheme 1

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(a) Excessive formamide, 150 °C, 6 h; (b) DMF, SOCl2, 80 °C, 25 h; (c) 2,4-dihydroxy-5-chlorobenzaldehyde, NaHCO3, KI, CH3CN, 60 °C, 50 h; (d) Cs2CO3, 3-(bromomethyl)benzonitrile, DMF, rt, 30 min; (e) SOCl2, 80°C; (f) 2,4-dihydroxy-5-chlorobenzaldehyde, NaHCO3, KI, MeCN, 60 °C, 50 h; (g) PdCl2(PPh3)2, KOAc, bis(pinacolato)diboron, 1,4-dioxane, 100 °C, 15 h; (h) Cs2CO3, 3-(bromomethyl)benzonitrile, DMF, rt, 30 min; (i) XPhos Pd G2, K3PO4, THF–water, 70 °C, 16 h; (j) appropriate amine, NaBH(OAc)3/NaBH3CN/NaBH4, HOAc, DCM, or DCM–MeOH, rt, overnight.

All of the target compounds were evaluated for their in vitro inhibitory activity against PD-1/PD-L1 interaction using the HTRF assay. As shown in Table 1, it was clearly observed that inhibitory activity of intermediate 9 (IC50 > 1000 nM) and compound A1 (IC50 > 1000 nM) on PD-1/PD-L1 interaction was significantly weaker than that of the compounds A2–A20 (IC50 = ∼20–390 nM), indicating that the presence of a tail with a suitable length was important for the compounds to maintain strong inhibitory activity. Accordingly, the effects of different tails on the inhibitory activity were further investigated. We found that introduction of alcohol hydroxyl in the tail was beneficial for enhancing inhibitory activity, such as A2 (IC50 = 37.68 nM) and A3 (IC50 = 47.18 nM) > A11 (IC50 = 48.50 nM) and A12 (IC50 = 51.49 nM), A17 (IC50 = 46.17 nM) and A18 (IC50 = 55.49 nM) > A15 (IC50 = 111.99 nM), A19 (IC50 = 75.82 nM) > A16 (IC50 = 166.70 nM). Compounds bearing two or three alcohol hydroxyls, A3–A7, displayed potent inhibitory activity with IC50 values ranging from 20 to 50 nM. Among them, A5 was the most potent with an IC50 value of 23.78 nM against PD-1/PD-L1 interaction, which was stronger than that of compound 6 (IC50 = 40.82 nM) but weaker than that of BMS-1166 (IC50 = 12.32 nM) and INCB086550 (IC50 = 12.13 nM), suggesting that further exploration on the tail is needed to identify a more potent compound. In addition, inhibitory activity of compounds A8 (IC50 = 100.55 nM) and A9 (IC50 = 61.37 nM) showed that replacement of the hydroxyl with methoxy and acetamido in the aminoethanol fragment resulted in a decrease in inhibitory activity, further demonstrating the importance of alcohol hydroxyl in the aminol fragment for inhibitory activity. Moreover, it was also observed that compound A10 (IC50 = 44.78 nM), obtained by methylating the sec-amino of aminoethanol fragment, showed a decreased inhibitory activity compared to A2 (IC50 = 37.68 nM). Furthermore, we investigated the effects of the lipophilic groups in the tail and their size on the inhibitory activity of the compounds. The results of A13–A16 (IC50 = ∼100–400 nM) showed that the introduction of rigid lipophilic groups and increase of their size significantly reduced the inhibitory activity, while the introduction of hydroxyl or oxygen atoms on these lipophilic groups to improve hydrophilicity enhanced the inhibitory activity, as shown in A17–A20 (IC50 = ∼40–70 nM). Finally, based on the above results, we concluded that the hydrophilic and flexible groups containing alcohol hydroxyl and secondary amino in the tail contributed significantly to the inhibitory activity of the compounds.

Table 1. Inhibitory Activity of Compounds i-9 and A1–A20 against the PD-1/PD-L1 Interaction.

graphic file with name ml4c00014_0006.jpg

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a

Data are displayed as averages from at least two independent experiments ± SD.

To further investigate the inhibitory activity of compounds against PD-1/PD-L1 interaction at the cellular level, compound A5 and a co-culture system of Jurkat-NFAT-PD-1 cells (Jurkat cells expressing PD-1 and carrying a reporter gene) and Hep3B-OS8-hPD-L1 cells (Hep3B cells expressing OS-8 and human PD-L1) were selected to perform a cell-based PD-1/PD-L1 blockade bioassay. We first carried out a cytotoxicity test of A5 on Jurkat cells for exploring the appropriate administration dose. As shown in Figure 3A, A5 showed no significant toxicity on jurkat cells at concentrations below 3.3 μM. Therefore, to avoid a potential toxic effect, the final concentrations of A5 were not more than 3.3 μM in the co-culture assay, while Keytruda was used as positive control to ensure the accuracy of the co-culture assay. As shown in Figure 3B, in the co-culture system, luminescence was inhibited by PD-1/PD-L1 interaction of Jurkat-NFAT-PD-1 cells and Hep3B-OS8-hPD-L1 cells. The addition of Keytruda blocked the PD-1/PD-L1 interaction and led to a significant increase in the luminescence intensity compared to the negative control, indicating that the co-culture model worked well. Furthermore, a dose-dependent increase in the luminescence intensity was observed with the addition of A5, suggesting that A5 could block the PD-1/PD-L1 interaction at the cellular level in a dose-dependent manner, and inhibition of A5 at 1.1 μM on the PD-1/PD-L1 interaction was comparable to Keytruda.

Figure 3.

Figure 3

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(A) Cell viability of control (medium), A5, and BMS-202 on Jurkat cells for 48 h detected by a CCK-8 assay. Data are shown as mean ± SEM, n = 3 (*P < 0.05, ***P < 0.001, ****P < 0.0001, ordinary one-way ANOVA, compared to control). (B) Luminescence intensity of control (medium), A5, BMS-202, and Keytruda in a co-culture of Jurkat-NFAT-PD-1 cells and Hep3B-OS8-hPD-L1 cells for 6 h. Data are shown as mean ± SEM, n ≥ 2 (*P < 0.05, **P < 0.01, ordinary one-way ANOVA).

To investigate the potential binding of A5 to PD-L1, a molecular docking study of A5 was performed. As shown in Figure 4, A5 was similar to the reported symmetric PD-L1 inhibitors and was located in the deep hydrophobic tunnel formed by the two monomers within the dimer. The 8-(o-tolyl)quinazoline moiety could replace the biphenyl core in biphenyl PD-L1 inhibitors, occupying a cylindrical hydrophobic channel composed of hydrophobic amino acids such as Met115 and Ala121, providing an important support for the skeleton merging strategy. The chlorophenyl and benzonitrile created π–π interactions with Tyr56 and Tyr123, stabilizing the binding to PD-L1. Moreover, 3-aminopropane-1,2-diol in the tail extended into the solvent region, and the sec-amino and alcohol hydroxyls created several key hydrogen bonding interactions with hydrophilic amino acid residues (Lys124, Asp122, and Thr20) around the binding pocket, respectively, further enhancing the binding of the compound to PD-L1. These above potential bindings of A5 to PD-L1 provided good evidence for its outstanding the inhibitory activity. Furthermore, based on the above docking results, we proposed some possible explanations for the changes in the activity of the compounds. The inhibitory activity of A5 that was weaker than that of INCB086550 and BMS-1166 could be attributed to the fact that the hydrogen-bonding interaction of A5 with Lys124 was weaker than the ionic interaction formed by the carboxy group in the tail of INCB086550 and BMS-1166 with Lys124. Compound A1 lacked a basic amino in the tail that could form an ionic interaction with ASP122 like compound A5, resulting in its significantly weaker inhibitory activity than that of A11–A16. In addition, the reduced inhibitory activity of compounds A13–A16 might be due to the fact that the tails of these compounds contained fewer hydrogen-bond donors and acceptors that were unfavorable for binding to hydrophilic amino acids around the binding pocket.

Figure 4.

Figure 4

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Docking analysis of compound A5 with the PD-L1 dimer (PDB: 8K5N; chain 1, green; chain 2, cyan). (A) The proposed binding mode of A5 with dimeric PD-L1. (B) Binding interactions of A5 with dimeric PD-L1.

In summary, we designed and synthesized a series of 8-(o-tolyl)quinazoline derivatives as small-molecule PD-L1 inhibitors by merging the core skeleton of 8-phenylquinazoline PD-L1 inhibitors identified in our previous study with those of reported biphenyl PD-L1 inhibitors. Among them, compound A5 exhibited the most potent inhibitory activity against PD-1/PD-L1 interaction with an IC50 value of 23.78 nM in the HTRF assay. The SARs revealed that the hydrophilic and flexible groups containing an alcohol hydroxyl and a secondary amino in the tail contributed significantly to the inhibitory activity of the compounds. Further investigation at the cellular level showed that A5 blocked the PD-1/PD-L1 interaction at a concentration of 1.1 μM in the co-culture system of Jurkat-NFAT-PD-1 cells and Hep3B-OS8-hPD-L1 cells with no significant cytotoxicity, which was comparable to Keytruda. Molecular docking analysis of A5 revealed the 8-(o-tolyl)quinazoline moiety could replace the biphenyl core in biphenyl PD-L1 inhibitors, occupying a cylindrical hydrophobic channel, and the chlorophenyl, benzonitrile, and 3-aminopropane-1,2-diol created multiple π–π and hydrogen bonding interactions with PD-L1, supporting the skeleton merging strategy and its outstanding inhibitory activity. These results suggest that compound A5 can serve as a promising lead compound for further investigation.

Acknowledgments

This work is supported by the Fujian Province Natural Science Foundation (2021J01309, China) and Fujian Provincial Health Technology Project (2020QNA060, China).

Glossary

Abbreviations

PD-1

programmed cell death-1

PD-L1

programmed cell death-ligand 1

mAbs

monoclonal antibodies

HTRF

homogenous time-resolved fluorescence

BMS

Bristol Myers Squibb

SARs

structure–activity relationships

IC50

50% inhibitory concentration

Tyr

tyrosine

Arg

arginase

Asp

aspartic acid

Thr

threonine

Ala

alanine

Met

methionine

Lys

lysine

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00014.

  • General chemistry and structural data, PD-1/PD-L1 HTRF binding assay, cell-based PD-1/PD-L1 blockade assay, molecular docking, and NMR spectra (PDF)

Author Contributions

# X.W. and H.L. contributed equally.

The authors declare no competing financial interest.

Supplementary Material

ml4c00014_si_001.pdf (8.5MB, pdf)

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Supplementary Materials

ml4c00014_si_001.pdf (8.5MB, pdf)

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