TYM-3-98, a novel selective inhibitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B-cell lymphomas

Si-Yue Lou; Fan-Li Zheng; Yong-Mei Tang; Ya-Nan Zheng; Jun Lu; Hai An; En-Jun Zhang; Sun-Liang Cui; Hua-Jun Zhao

doi:10.1016/j.lfs.2024.122662

TYM-3-98, a novel selective inhibitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B-cell lymphomas

Life Sci. 2024 Apr 24:347:122662. doi: 10.1016/j.lfs.2024.122662. Online ahead of print.

Authors

Si-Yue Lou¹, Fan-Li Zheng², Yong-Mei Tang³, Ya-Nan Zheng⁴, Jun Lu⁴, Hai An⁵, En-Jun Zhang⁴, Sun-Liang Cui⁶, Hua-Jun Zhao⁷

Affiliations

¹ School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311403, China; Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Binwen Rd, Hangzhou, Zhejiang 310053, China.
² School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311403, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China.
³ Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
⁴ School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311403, China.
⁵ Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Binwen Rd, Hangzhou, Zhejiang 310053, China.
⁶ Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: slcui@zju.edu.cn.
⁷ School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311403, China; Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Binwen Rd, Hangzhou, Zhejiang 310053, China. Electronic address: zhj@zcmu.edu.cn.

PMID: 38670450
DOI: 10.1016/j.lfs.2024.122662

Abstract

Aims: PI3Kδ is expressed predominately in leukocytes and is commonly found to be aberrantly activated in human B-cell lymphomas. Although PI3Kδ has been intensively targeted for discovering anti-lymphoma drugs, the application of currently approved PI3Kδ inhibitors has been limited due to unwanted systemic toxicities, thus warranting the development of novel PI3Kδ inhibitors with new scaffolds.

Main methods: We designed TYM-3-98, an indazole derivative, and evaluated its selectivity for all four PI3K isoforms, as well as its efficacy against various B-cell lymphomas both in vitro and in vivo.

Key findings: We identified TYM-3-98 as a highly selective PI3Kδ inhibitor over other PI3K isoforms at both molecular and cellular levels. It showed superior antiproliferative activity in several B-lymphoma cell lines compared with the approved first-generation PI3Kδ inhibitor idelalisib. TYM-3-98 demonstrated a concentration-dependent PI3K/AKT/mTOR signaling blockage followed by apoptosis induction. In vivo, TYM-3-98 showed good pharmaceutical properties and remarkably reduced tumor growth in a human lymphoma xenograft model and a mouse lymphoma model.

Significance: Our findings establish TYM-3-98 as a promising PI3Kδ inhibitor for the treatment of B-cell lymphoma.

Keywords: B-cell lymphoma; Indazole derivatives; PI3K/AKT/mTOR; PI3Kδ; TYM-3-98.