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.
- 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: [email protected].
- 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: [email protected].
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.