Development of Inhibitors Targeting the V-Domain Ig Suppressor of T Cell Activation Signal Pathway

Zheng, Shuai; Zhang, Kuojun; Zhang, Xiangyu; Xiao, Yibei; Wang, Tianyu; Jiang, Sheng

doi:10.1021/acs.jmedchem.2c00803

Cited by 3 publications

(3 citation statements)

References 73 publications

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“…Tumor occurrence and development are largely driven by the activation of inhibitory immune checkpoint pathways, which impair the antitumor activities of T cells. Blocking the VISTA pathway can reactivate T cells and enhance their cytotoxicity against tumor cells . SKOV3 cells, which express high levels of VISTA protein, were cocultured with PBMCs.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors

Sun,

He,

Wang

et al. 2024

J. Med. Chem.

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VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidinebased VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a K D value of 0.49 ± 0.20 μM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors

Sun,

He,

Wang

et al. 2024

J. Med. Chem.

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“…Hong et al. fabricated tumor tissue slices from patients with clear cell renal cell carcinoma (ccRCC) to evaluate the antitumor effectiveness of a V‐domain Ig suppressor of T‐cell activation (VISTA) inhibitor, which is a candidate immune checkpoint inhibitor (ICI) 87 . The results indicated that all tested samples responded to the anti‐VISTA monoclonal antibody and produced TNF‐α, with 20% of ccRCC samples showing a synergistic effect when treated with a combination of VISTA and PD‐1 inhibitors.…”

Section: Application Of Civms In Drug Development and Precision Medicinementioning

confidence: 99%

Complex in vitro model: A transformative model in drug development and precision medicine

Wang,

Hu,

et al. 2024

Clinical Translational Sci

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In vitro and in vivo models play integral roles in preclinical drug research, evaluation, and precision medicine. In vitro models primarily involve research platforms based on cultured cells, typically in the form of two‐dimensional (2D) cell models. However, notable disparities exist between 2D cultured cells and in vivo cells across various aspects, rendering the former inadequate for replicating the physiologically relevant functions of human or animal organs and tissues. Consequently, these models failed to accurately reflect real‐life scenarios post‐drug administration. Complex in vitro models (CIVMs) refer to in vitro models that integrate a multicellular environment and a three‐dimensional (3D) structure using bio‐polymer or tissue‐derived matrices. These models seek to reconstruct the organ‐ or tissue‐specific characteristics of the extracellular microenvironment. The utilization of CIVMs allows for enhanced physiological correlation of cultured cells, thereby better mimicking in vivo conditions without ethical concerns associated with animal experimentation. Consequently, CIVMs have gained prominence in disease research and drug development. This review aimed to comprehensively examine and analyze the various types, manufacturing techniques, and applications of CIVM in the domains of drug discovery, drug development, and precision medicine. The objective of this study was to provide a comprehensive understanding of the progress made in CIVMs and their potential future use in these fields.

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“…Deficiency or blockade of VISTA enhances antitumor immunity in multiple tumor types, such as melanoma, pancreatic, prostate, and colon carcinoma. − VISTA is also an important target for autoimmune diseases and its activation could be effective for the treatment of autoimmune diseases such as lupus. − Currently, only few small-molecule antagonists or agonists of VISTA have been identified. Clinical trials are in progress of four VISTA-targeting compounds, including three anti-VISTA mAbs (CI-8993, W0180, and HMBD-002) and CA-170. − However, recent studies reported that CA-170, the first clinical small-molecule inhibitor of PD-L1 and VISTA, exhibits weak binding affinity to PD-L1 and VISTA. , …”

Section: Introductionmentioning

confidence: 99%

Novel Benzimidazoles as Potent Small-Molecule Inhibitors and Degraders of V-Domain Ig Suppressor of T-Cell Activation (VISTA)

Wang,

Zhang

et al. 2023

J. Med. Chem.

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The V-domain Ig suppressor of T-cell activation (VISTA) is a promising negative immune checkpoint and plays a critical role in the regulation of the quiescence of naïve T lymphocytes. Most patients however do not experience durable disease control from current immune checkpoint inhibitors and discovery of inhibitors targeting novel immune checkpoints is necessary. Herein, we report our discovery and optimization of benzimidazoles as the bifunctional inhibitors of VISTA. Compound 1 is identified as a bifunctional inhibitor targeting VISTA, which shows good binding affinity to VISTA and induces VISTA degradation in HepG2 cells through an autophagic mechanism. Compound 1 rescues VISTA-mediated immunosuppression effectively and enhances antitumor activity of immune cells. 1 activates the antitumor immunity in vivo and suppresses tumor growth in a CT26 mouse model significantly. Our results show that compound 1 is a promising VISTA inhibitor and degrader and offers novel approach for cancer immunotherapy through VISTA degradation.

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Development of Inhibitors Targeting the V-Domain Ig Suppressor of T Cell Activation Signal Pathway

Cited by 3 publications

References 73 publications

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors

Complex in vitro model: A transformative model in drug development and precision medicine

Novel Benzimidazoles as Potent Small-Molecule Inhibitors and Degraders of V-Domain Ig Suppressor of T-Cell Activation (VISTA)

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