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Discovery of novel pyridone-benzamide derivatives possessing a 1-methyl-2-benzimidazolinone moiety as potent EZH2 inhibitors for the treatment of B-cell lymphomas.
Wu, Di; Zeng, Xiaoyi; Zhao, Yuanhao; Qin, Mingze; Gong, Ping.
Afiliación
  • Wu D; Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • Zeng X; Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • Zhao Y; Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • Qin M; Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: qinmingze001@126.com.
  • Gong P; Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: gongpinggp@126.com.
Bioorg Med Chem ; 105: 117725, 2024 May 01.
Article en En | MEDLINE | ID: mdl-38640588
ABSTRACT
Enhancer of zeste homolog 2 (EZH2) is a promising therapeutic target for diffuse large B-cell lymphoma. In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure-activity relationship at enzymatic and cellular levels, compound N40 was identified. Biochemical assays showed that compound N40 (IC50 = 0.32 nM) exhibited superior inhibitory activity against EZH2 WT, compared with 1 (IC50 = 1.20 nM), and high potency against EZH2 Y641 mutants (EZH2 Y641F, IC50 = 0.03 nM; EZH2 Y641N, IC50 = 0.08 nM), which were approximately 10-fold more active than those of 1 (EZH2 Y641F, IC50 = 0.37 nM; EZH2 Y641N, IC50 = 0.85 nM). Furthermore, compound N40 (IC50 = 3.52 ±â€¯1.23 nM) effectively inhibited the proliferation of Karpas-422 cells and was more potent than 1 (IC50 = 35.01 ±â€¯1.28 nM). Further cellular experiments showed that N40 arrested Karpas-422 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Moreover, N40 inhibited the trimethylation of lysine 27 on histone H3 (H3K27Me3) in Karpas-422 cells bearing the EZH2 Y641N mutant. Additionally, N40 (T1/2 = 177.69 min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2 = 7.97 min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridonas / Benzamidas / Ensayos de Selección de Medicamentos Antitumorales / Proliferación Celular / Proteína Potenciadora del Homólogo Zeste 2 / Antineoplásicos Límite: Humans Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridonas / Benzamidas / Ensayos de Selección de Medicamentos Antitumorales / Proliferación Celular / Proteína Potenciadora del Homólogo Zeste 2 / Antineoplásicos Límite: Humans Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido