Discovery of quinazoline derivatives as novel small-molecule inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction

Wang, Yu; Huang, Kun; Gao, Yali; Yuan, Dandan; Lin, Ling; Liu, Jie‐Qing; Wu, Si‐Hai; Chen, Roufen; Li, He; Xiong, Yizu; Liu, Han; Ma, Junjie

doi:10.1016/j.ejmech.2021.113998

Cited by 13 publications

(11 citation statements)

References 25 publications

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“…The hit compound was then improved through SAR studies, and a series of resorcinol dibenzyl ethers were synthetized, with compound NP19 ( 22 ) in Figure 5 inhibiting the PD-1/PD-L1 interaction with an IC 50 value of 12.5 nM in Homogeneous Time-Resolved Fluorescence (HTRF) binding assays. Also based on the pharmacophoric model of BMS compounds, and with the use of molecular docking as a corroborative technique [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ], Dai and co-workers [ 74 ] obtained 1-methyl-1H-pyrazolo [4,3-b] pyridine derivatives, with the best compound, D38 ( 23 ) ( Figure 5 ), having an IC 50 value of 9.6 nM. Liu et al [ 75 ] reported benzo[c][1,2,5]oxadiazole derivatives, with molecule L7 ( 24 ) in Figure 5 exhibiting an IC 50 value of 1.8 nM.…”

Section: Computational Methods For Predicting Checkpoint Inhibitorsmentioning

confidence: 99%

Computational Approaches Drive Developments in Immune-Oncology Therapies for PD-1/PD-L1 Immune Checkpoint Inhibitors

Sobral

Luz

Almeida

et al. 2023

IJMS

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Computational approaches in immune-oncology therapies focus on using data-driven methods to identify potential immune targets and develop novel drug candidates. In particular, the search for PD-1/PD-L1 immune checkpoint inhibitors (ICIs) has enlivened the field, leveraging the use of cheminformatics and bioinformatics tools to analyze large datasets of molecules, gene expression and protein–protein interactions. Up to now, there is still an unmet clinical need for improved ICIs and reliable predictive biomarkers. In this review, we highlight the computational methodologies applied to discovering and developing PD-1/PD-L1 ICIs for improved cancer immunotherapies with a greater focus in the last five years. The use of computer-aided drug design structure- and ligand-based virtual screening processes, molecular docking, homology modeling and molecular dynamics simulations methodologies essential for successful drug discovery campaigns focusing on antibodies, peptides or small-molecule ICIs are addressed. A list of recent databases and web tools used in the context of cancer and immunotherapy has been compilated and made available, namely regarding a general scope, cancer and immunology. In summary, computational approaches have become valuable tools for discovering and developing ICIs. Despite significant progress, there is still a need for improved ICIs and biomarkers, and recent databases and web tools have been compiled to aid in this pursuit.

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Section: Computational Methods For Predicting Checkpoint Inhibitorsmentioning

confidence: 99%

Computational Approaches Drive Developments in Immune-Oncology Therapies for PD-1/PD-L1 Immune Checkpoint Inhibitors

Sobral

Luz

Almeida

et al. 2023

IJMS

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“…In recent years, important advances have been made in the field of PD-1/PD-L1 small-molecule inhibitors, for example, the arylmethylamine (Figure , highlighted in red) and biphenyl skeleton-based compounds (Figure , highlighted in blue) discovered by Bristol-Myers Squibb (BMS) as exemplified by BMS-202 . Current small-molecule PD-L1 inhibitors were mostly developed based on the BMS compounds. − Qin et al reported the discovery of a 4-arylindoline analogue ( A30 , Figure ) containing a thiazole moiety with an IC 50 of 11.2 nM . Meanwhile, researchers from China Pharmaceutical University (Jiang, Lai, Sun, etc.)…”

Section: Introductionmentioning

confidence: 99%

Discovery and Crystallography Study of Novel Biphenyl Ether and Oxadiazole Thioether (Non-Arylmethylamine)-Based Small-Molecule PD-1/PD-L1 Inhibitors as Immunotherapeutic Agents

Liu,

Cheng,

Yuan

et al. 2023

J. Med. Chem.

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Current small-molecule PD-1/PD-L1 inhibitors are mainly based on the arylmethylamine/biphenyl core scaffold. Herein, we designed for the first time a series of non-arylmethylamine analogues (oxadiazole thioether derivatives) as smallmolecule PD-1/PD-L1 inhibitors. Among them, compound LP23 exhibited the most potent PD-L1 inhibitory activity with an IC 50 of 16.7 nM, 3.2-fold better than the lead BMS-202 (IC 50 = 53.6 nM). The X-ray crystal structure of LP23 in complex with PD-L1 was solved at a resolution of 2.6 Å, which further confirmed the high binding affinity of LP23 to PD-L1. In the HepG2/Jurkat T cell coculture model, LP23 effectively promoted HepG2 cell death by restoring the immune function of T cells. In addition, LP23 showed excellent in vivo antitumor efficacy (TGI = 88.6% at 30 mg/kg) and benign toxicity profiles in a B16-F10 tumor model by modulating PD-L1. In summary, LP23 represents the first nonarylmethylamine-based small-molecule PD-1/PD-L1 inhibitor worthy of further investigation.

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“…They reported derivatives of (2-methyl-3-biphenylyl) methanol and [3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl] methanol with strong binding affinities to PD-L1, providing crystal structures for complexes of PD-L1 and inhibitors of these two classes . Based on the latter, other research groups used the ring fusion strategy to synthesize benzo[ d ]isothiazole derivatives and quinazoline derivatives with strong inhibition of PD-1/PD-L1 interaction. , None of these molecules have been approved by FDA. However, several of these molecules are currently being tested in clinical trials. , …”

Section: Introductionmentioning

confidence: 99%

“…12 Based on the latter, other research groups used the ring fusion strategy to synthesize benzo [d]isothiazole derivatives and quinazoline derivatives with strong inhibition of PD-1/PD-L1 interaction. 14,15 None of these molecules have been approved by FDA. However, several of these molecules are currently being tested in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Virtual Screening and Biological Evaluation of Potential PD-1/PD-L1 Immune Checkpoint Inhibitors as Anti-Hepatocellular Carcinoma Agents

Kamal,

Badary,

Omran

et al. 2023

ACS Omega

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Blockade of the programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) immune checkpoint pathway is an efficient immunotherapeutic modality that provided significant advances in cancer treatment especially in solid tumors highly resistant to traditional therapy. Monoclonal antibodies (mAbs) and small-molecule inhibitors are the two main strategies used to block this axis with mAbs suffering from many limitations. Accordingly, the current alternative is the development of smallmolecule PD-1/PD-L1 inhibitors. Here, we present a sequential virtual screening (VS) protocol involving pharmacophore screening followed by molecular docking for the discovery of novel PD-L1 inhibitors. The VS protocol resulted in the discovery of eight novel compounds. A 100 ns MD simulation showed two compounds, H4 and H6, exhibiting a stable binding mode at the PD-L1 dimer interface. Upon evaluation of their immunological activities, the two compounds induced higher cytokines levels (IL-2, IL-6, and INF-γ) relative to BMS-202, 72 h post treatment of PBMCs of HCC patients. Thus, the discovered hits represent potential leads for the development of novel classes targeting the PD-L1 receptor as anti-hepatocellular carcinoma agents.

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Discovery of quinazoline derivatives as novel small-molecule inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction

Cited by 13 publications

References 25 publications

Computational Approaches Drive Developments in Immune-Oncology Therapies for PD-1/PD-L1 Immune Checkpoint Inhibitors

Computational Approaches Drive Developments in Immune-Oncology Therapies for PD-1/PD-L1 Immune Checkpoint Inhibitors

Discovery and Crystallography Study of Novel Biphenyl Ether and Oxadiazole Thioether (Non-Arylmethylamine)-Based Small-Molecule PD-1/PD-L1 Inhibitors as Immunotherapeutic Agents

Virtual Screening and Biological Evaluation of Potential PD-1/PD-L1 Immune Checkpoint Inhibitors as Anti-Hepatocellular Carcinoma Agents

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