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Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits Potent Efficacy as Monotherapy for Primary Central Nervous System Lymphoma

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Abstract

Background

The efficacy of systemic treatment for primary central nervous system lymphoma (PCNSL) is limited because of the blood–brain barrier (BBB) and the ineffectiveness of chemotherapy. The dual PI3K/HDAC inhibitor BEBT-908 has exhibited favorable in vivo distribution and activity in various cancers.

Objectives

The aims of this study were to assess the efficacy of BEBT-908 in brain orthotopic mouse models of hematological malignancies, to investigate its pharmacologic properties, and to elucidate the underlying mechanism of action.

Methods

We evaluated the anticancer activity of BEBT-908 in various hematological malignancies through cell viability assays. The impact of BEBT-908 on c-Myc expression and ferroptosis signaling pathways was assessed using Western blotting, qPCR, ROS detection, GSH/GSSG detection, and IHC. Pharmacokinetic and pharmacodynamic profiles were assessed through LC–MS/MS and Western blotting. The effects of BEBT-908 in vivo were examined using xenografts and brain orthotopic mouse models.

Results

Our findings demonstrate that BEBT-908 exhibits promising anti-tumor activity in vitro and in vivo across multiple subtypes of hematological malignancies. Furthermore, BEBT-908 exhibits excellent BBB penetration and inhibits tumor growth in a brain orthotopic lymphoma model with prolonged survival of host mice. Mechanistically, BEBT-908 downregulated c-Myc expression, which contributed to ferroptosis, ultimately leading to tumor shrinkage.

Conclusion

Our study provides robust evidence for the dual PI3K/HDAC inhibitor BEBT-908 as an effective anti-cancer agent for PCNSL.

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Authors and Affiliations

  1. Guangdong Provincial People’s Hospital Affiliated to Southern Medical University, Guangdong Academy of Medical Sciences, No. 123 Huifu West Road, Guangzhou, 510080, Guangdong, China

    Ning Wang, Lu Pan, Feili Chen & Wenyu Li

  2. College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, China

    Fushun Fan

  3. Guangzhou BeBetter Med Inc., No. 25 Yayingshi Road, Guangzhou, 510660, Guangdong, China

    Zhenxian Mo, Minhua Zhou, Xiaolan Ye, Xinjian Liu, Xiong Cai, Changgeng Qian, Yan Xiong & Fushun Fan

  4. College of Life Science and Technology, Jinan University, 601 Huangpu Avenue West, Guangzhou, China

    Zhenxian Mo

  5. School of Medicine, South China University of Technology, Guangzhou, China

    Ning Wang, Lu Pan & Wenyu Li

  6. Curis, Inc., Lexington, MA, USA

    Xiong Cai & Changgeng Qian

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  1. Ning Wang
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Corresponding authors

Correspondence to Fushun Fan or Wenyu Li.

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Funding

This study is funded by National Science and Technology Major Project of China (2016ZX09101002), Guangdong Pearl River Talents Plan (2014ZT05Y232), Guangzhou Municipal Science and Technology Project (201909020004).

Conflict of interest

C. Qian and X. Cai are inventors of BEBT-908 and founders of Guangzhou BeBetter Medicine Technology Co., Ltd. N.Wang, Z.Mo, L.Pan, M.Zhou, X.Ye, X.Liu, F.Chen, Y. Xiong, F.Fan, W.Li declare that they have no conflicts of interest that might be relevant to the contents of this article.

Institutional Review Board Statement

The animal study was approved by Curis Inc and Ruiye Animal Model Inc Animal Use and Care Committee.

Consent to Participate and Publish

Not applicable due to the study being preclinical in nature.

Data Availability

The data generated in the present study are included in the article and the Online Supplementary Materials.

Code Availability

Not applicable.

Author Contributions

Conceptualization: WL, FF, XL, CQ; Methodology: NW, ZM, LP, MZ, XY, FC; Validation: WL, FF, NW; Formal Analysis: FF, NW; Investigation: WL, FF; Resources: WL, CQ, XC, YX; Data curation: FF, NW; Writing—original draft preparation: NW, FF; Writing—review and editing: FF, XL; Supervision: FF, XL; Project administration: WL, FF; Funding acquisition: CQ.

Additional information

Xiong Cai and Changgeng Qian are former employees of Curis, Inc.

Supplementary Information

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Supplementary file1 (PDF 117 KB)

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Wang, N., Mo, Z., Pan, L. et al. Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits Potent Efficacy as Monotherapy for Primary Central Nervous System Lymphoma. Targ Oncol 18, 941–952 (2023). https://doi.org/10.1007/s11523-023-01006-z

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