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

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

  • Life Sci. 2024 Jun 15:347:122662. doi: 10.1016/j.lfs.2024.122662.
Si-Yue Lou 1,  Fan-Li Zheng 2,  Yong-Mei Tang 3,  Ya-Nan Zheng 4,  Jun Lu 4,  Hai An 5,  En-Jun Zhang 4,  Sun-Liang Cui 6,  Hua-Jun Zhao 7
Affiliations

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.

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