TYM-3-98, a novel selective inhibitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B-cell lymphomas.
Life Sci
; 347: 122662, 2024 Jun 15.
Article
en En
| MEDLINE
| ID: mdl-38670450
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. MAINMETHODS:
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. KEYFINDINGS:
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.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Linfoma de Células B
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Ensayos Antitumor por Modelo de Xenoinjerto
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Fosfatidilinositol 3-Quinasa Clase I
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Inhibidores de las Quinasa Fosfoinosítidos-3
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Antineoplásicos
Idioma:
En
Revista:
Life Sci
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Life sci. (1973)
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Life sciences (1973)
Año:
2024
Tipo del documento:
Article