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A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma.
Jana, Sadhan; Shang, Jialin; Hong, Jun Young; Fenwick, Michael K; Puri, Rishi; Lu, Xuan; Melnick, Ari M; Li, Meng; Lin, Hening.
Afiliação
  • Jana S; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
  • Shang J; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
  • Hong JY; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
  • Fenwick MK; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
  • Puri R; College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, United States.
  • Lu X; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
  • Melnick AM; Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, New York 10065, United States.
  • Li M; Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, New York 10065, United States.
  • Lin H; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
J Med Chem ; 67(17): 15428-15437, 2024 Sep 12.
Article em En | MEDLINE | ID: mdl-39191393
ABSTRACT
Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous cancers that still require better and less toxic treatments. SIRT3, a member of the sirtuin family of NAD+-dependent protein deacylase, is critical for DLBCL growth and survival. A mitochondria-targeted SIRT3 small-molecule inhibitor, YC8-02, exhibits promising activity against DLBCL. However, YC8-02 has several limitations including poor solubility. Here, we report our medicinal chemistry efforts that led to an improved mitochondria-targeted SIRT3 inhibitor, SJ-106C, achieved by using a triethylammonium group, which helps to increase both solubility and SIRT3 inhibition potency. SJ-106C, while still inhibiting SIRT1 and SIRT2, is enriched in the mitochondria to help with SIRT3 inhibition. It is more active against DLBCL than other solid tumor cells and effectively inhibits DLBCL xenograft tumor growth. The findings provide useful insights for the development of SIRT3 inhibitors and mitochondrial targeting agents and further support the notion that SIRT3 is a promising druggable target for DLBCL.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfoma Difuso de Grandes Células B / Sirtuína 3 / Mitocôndrias / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfoma Difuso de Grandes Células B / Sirtuína 3 / Mitocôndrias / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos