Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction

Wang, Fengling; Ye, Wenling; He, Yongxing; Zhong, Haiyang; Zhu, Yongchang; Han, Jianting; Gong, Xiaoqing; Tian, Yanan; Wang, Yuwei; Wang, Shuang; Ji, Shaoping; Liu, Huanxiang; Yao, Xiaojun

doi:10.3390/ijms24043971

Open AccessArticle

Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction

by

Fengling Wang

^1,2,†

,

Wenling Ye

^2,†,

Yongxing He

³,

Haiyang Zhong

¹,

Yongchang Zhu

¹,

Jianting Han

¹,

Xiaoqing Gong

¹,

Yanan Tian

⁴,

Yuwei Wang

⁵

,

Shuang Wang

¹,

Shaoping Ji

²,

Huanxiang Liu

^4,*

and

Xiaojun Yao

^1,6,*

¹

College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China

²

Henan International Joint Laboratory for Nuclear Protein Regulation, Cell Signal Transduction Laboratory, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China

³

Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, China

⁴

Faculty of Applied Science, Macao Polytechnic University, Macao 999078, China

⁵

College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046, China

⁶

State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau 999078, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2023, 24(4), 3971; https://doi.org/10.3390/ijms24043971

Submission received: 20 September 2022 / Revised: 20 December 2022 / Accepted: 27 December 2022 / Published: 16 February 2023

(This article belongs to the Special Issue Drug Design and Virtual Screening 2.0)

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Abstract

Targeting of the PD-1/PD-L1 immunologic checkpoint is believed to have provided a real breakthrough in the field of cancer therapy in recent years. Due to the intrinsic limitations of antibodies, the discovery of small-molecule inhibitors blocking PD-1/PD-L1 interaction has gradually opened valuable new avenues in the past decades. In an effort to discover new PD-L1 small molecular inhibitors, we carried out a structure-based virtual screening strategy to rapidly identify the candidate compounds. Ultimately, CBPA was identified as a PD-L1 inhibitor with a K_D value at the micromolar level. It exhibited effective PD-1/PD-L1 blocking activity and T-cell-reinvigoration potency in cell-based assays. CBPA could dose-dependently elevate secretion levels of IFN-γ and TNF-α in primary CD4⁺ T cells in vitro. Notably, CBPA exhibited significant in vivo antitumor efficacy in two different mouse tumor models (a MC38 colon adenocarcinoma model and a melanoma B16F10 tumor model) without the induction of observable liver or renal toxicity. Moreover, analyses of the CBPA-treated mice further showed remarkably increased levels of tumor-infiltrating CD4⁺ and CD8⁺ T cells and cytokine secretion in the tumor microenvironment. A molecular docking study suggested that CBPA embedded relatively well into the hydrophobic cleft formed by dimeric PD-L1, occluding the PD-1 interaction surface of PD-L1. This study suggests that CBPA could work as a hit compound for the further design of potent inhibitors targeting the PD-1/PD-L1 pathway in cancer immunotherapy.

Keywords: PD-1; PD-L1; small-molecule inhibitor; CBPA; cancer immunotherapy

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MDPI and ACS Style

Wang, F.; Ye, W.; He, Y.; Zhong, H.; Zhu, Y.; Han, J.; Gong, X.; Tian, Y.; Wang, Y.; Wang, S.; et al. Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction. Int. J. Mol. Sci. 2023, 24, 3971. https://doi.org/10.3390/ijms24043971

AMA Style

Wang F, Ye W, He Y, Zhong H, Zhu Y, Han J, Gong X, Tian Y, Wang Y, Wang S, et al. Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction. International Journal of Molecular Sciences. 2023; 24(4):3971. https://doi.org/10.3390/ijms24043971

Chicago/Turabian Style

Wang, Fengling, Wenling Ye, Yongxing He, Haiyang Zhong, Yongchang Zhu, Jianting Han, Xiaoqing Gong, Yanan Tian, Yuwei Wang, Shuang Wang, and et al. 2023. "Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction" International Journal of Molecular Sciences 24, no. 4: 3971. https://doi.org/10.3390/ijms24043971

APA Style

Wang, F., Ye, W., He, Y., Zhong, H., Zhu, Y., Han, J., Gong, X., Tian, Y., Wang, Y., Wang, S., Ji, S., Liu, H., & Yao, X. (2023). Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction. International Journal of Molecular Sciences, 24(4), 3971. https://doi.org/10.3390/ijms24043971

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Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction

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