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A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma
Sadhan Jana1, Jialin Shang1, Jun Young Hong1
1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
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.
Insights
Researchers developed SJ-106C, a novel SIRT3 inhibitor, to improve treatments for diffuse large B-cell lymphoma (DLBCL). This new drug enhances solubility and potency, showing promise against DLBCL tumors.
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- Diffuse large B-cell lymphomas (DLBCLs) are aggressive cancers with unmet treatment needs.
- Sirtuin 3 (SIRT3) is crucial for DLBCL cell growth and survival.
- Existing mitochondria-targeted SIRT3 inhibitors like YC8-02 have limitations, such as poor solubility.
Purpose of the Study:
- To develop an improved mitochondria-targeted SIRT3 inhibitor with enhanced solubility and potency.
- To evaluate the efficacy of the novel inhibitor, SJ-106C, against DLBCL.
Main Methods:
- Medicinal chemistry optimization of YC8-02 to create SJ-106C, incorporating a triethylammonium group.
- Assessment of SJ-106C's solubility, SIRT3 inhibition potency, and cellular activity against DLBCL and other cancer cells.
- Evaluation of SJ-106C's efficacy in inhibiting DLBCL xenograft tumor growth in vivo.
Main Results:
- SJ-106C demonstrated increased solubility and enhanced SIRT3 inhibition potency compared to YC8-02.
- SJ-106C exhibited greater activity against DLBCL cells than against other solid tumor cells.
- SJ-106C effectively suppressed DLBCL xenograft tumor growth.
Conclusions:
- SJ-106C represents a promising advancement in mitochondria-targeted SIRT3 inhibitors for DLBCL treatment.
- SIRT3 is a viable and druggable target for developing novel DLBCL therapies.
- The findings offer valuable insights for designing future mitochondrial-targeting agents.
