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A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Sep 12; Vol. 67 (17), pp. 15428-15437. Date of Electronic Publication: 2024 Aug 27. - Publication Year :
- 2024
-
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 <superscript>+</superscript> -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.
- Subjects :
- Humans
Animals
Cell Line, Tumor
Mice
Xenograft Model Antitumor Assays
Cell Proliferation drug effects
Structure-Activity Relationship
Sirtuin 3 antagonists & inhibitors
Sirtuin 3 metabolism
Lymphoma, Large B-Cell, Diffuse drug therapy
Lymphoma, Large B-Cell, Diffuse pathology
Lymphoma, Large B-Cell, Diffuse metabolism
Mitochondria drug effects
Mitochondria metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 39191393
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c01053