Dataset Information

Artificial intelligence-powered discovery of small molecules inhibiting CTLA-4 in cancer.

ABSTRACT:

Background/objectives

Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4.

Subjects/methods

In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the hits molecules with biochemical, biophysical, immunological, and experimental animal assays.

Results

The primary hits obtained from the virtual screening were successfully validated in vitro and in vivo. We then optimized lead compounds and obtained inhibitors (inhibitory concentration, 1 micromole) that disrupted the CTLA-4/CD80 interaction without degrading CTLA-4.

Conclusions

Several compounds inhibited tumor development prophylactically and therapeutically in syngeneic and CTLA-4-humanized mice. Our findings support using AI-based frameworks to design small molecules targeting immune checkpoints for cancer therapy.

SUBMITTER: Sobhani N

PROVIDER: S-EPMC10838660 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

Artificial intelligence-powered discovery of small molecules inhibiting CTLA-4 in cancer.

Sobhani Navid N Tardiel-Cyril Dana Rae DR Chai Dafei D Generali Daniele D Li Jian-Rong JR Vazquez-Perez Jonathan J Lim Jing Ming JM Morris Rachel R Bullock Zaniqua N ZN Davtyan Aram A Cheng Chao C Decker William K WK Li Yong Y

BJC reports 20240123

<h4>Background/objectives</h4>Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86 ...[more]

PMID: 38312352

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Dataset Information

Artificial intelligence-powered discovery of small molecules inhibiting CTLA-4 in cancer.

Background/objectives

Subjects/methods

Results

Conclusions

Publications

Artificial intelligence-powered discovery of small molecules inhibiting CTLA-4 in cancer.

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