Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies
Genetic ablation as well as pharmacological inhibition of sirtuin 2 (SIRT2), an NAD<sup>+</sup>-dependent protein deacylase, have therapeutic effects in various cancers and neurodegenerative diseases. Previously, we described the discovery of a dual SIRT1/SIRT2 inhibitor called cambinol...
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MDPI AG
2020-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/3/455 |
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| author | Sarwat Chowdhury Smitha Sripathy Alyssa A. Webster Angela Park Uyen Lao Joanne H. Hsu Taylor Loe Antonio Bedalov Julian A. Simon |
| author_facet | Sarwat Chowdhury Smitha Sripathy Alyssa A. Webster Angela Park Uyen Lao Joanne H. Hsu Taylor Loe Antonio Bedalov Julian A. Simon |
| author_sort | Sarwat Chowdhury |
| collection | DOAJ |
| description | Genetic ablation as well as pharmacological inhibition of sirtuin 2 (SIRT2), an NAD<sup>+</sup>-dependent protein deacylase, have therapeutic effects in various cancers and neurodegenerative diseases. Previously, we described the discovery of a dual SIRT1/SIRT2 inhibitor called cambinol (IC<sub>50</sub> 56 and 59 µM, respectively), which showed cytotoxic activity against cancer cells in vitro and a marked anti-proliferative effect in a Burkitt lymphoma mouse xenograft model. A number of recent studies have shown a protective effect of SIRT1 and SIRT3 in neurodegenerative and metabolic diseases as well as in certain cancers prompting us to initiate a medicinal chemistry effort to develop cambinol-based SIRT2-specific inhibitors devoid of SIRT1 or SIRT3 modulating activity. Here we describe potent cambinol-based SIRT2 inhibitors, several of which show potency of ~600 nM with >300 to >800-fold selectivity over SIRT1 and 3, respectively. In vitro, these inhibitors are found to be toxic to lymphoma and epithelial cancer cell lines. In particular, compounds <b>55</b> (IC<sub>50</sub> SIRT2 0.25 µM and <25% inhibition at 50 µM against SIRT1 and SIRT3) and <b>56</b> (IC<sub>50</sub> SIRT2 0.78 µM and <25% inhibition at 50 µM against SIRT1 and SIRT3) showed apoptotic as well as strong anti-proliferative properties against B-cell lymphoma cells. |
| first_indexed | 2024-04-13T14:28:34Z |
| format | Article |
| id | doaj.art-701f631691e645a6a9f2f45d50e49e0b |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-13T14:28:34Z |
| publishDate | 2020-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-701f631691e645a6a9f2f45d50e49e0b2022-12-22T02:43:15ZengMDPI AGMolecules1420-30492020-01-0125345510.3390/molecules25030455molecules25030455Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other MalignanciesSarwat Chowdhury0Smitha Sripathy1Alyssa A. Webster2Angela Park3Uyen Lao4Joanne H. Hsu5Taylor Loe6Antonio Bedalov7Julian A. Simon8Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAGenetic ablation as well as pharmacological inhibition of sirtuin 2 (SIRT2), an NAD<sup>+</sup>-dependent protein deacylase, have therapeutic effects in various cancers and neurodegenerative diseases. Previously, we described the discovery of a dual SIRT1/SIRT2 inhibitor called cambinol (IC<sub>50</sub> 56 and 59 µM, respectively), which showed cytotoxic activity against cancer cells in vitro and a marked anti-proliferative effect in a Burkitt lymphoma mouse xenograft model. A number of recent studies have shown a protective effect of SIRT1 and SIRT3 in neurodegenerative and metabolic diseases as well as in certain cancers prompting us to initiate a medicinal chemistry effort to develop cambinol-based SIRT2-specific inhibitors devoid of SIRT1 or SIRT3 modulating activity. Here we describe potent cambinol-based SIRT2 inhibitors, several of which show potency of ~600 nM with >300 to >800-fold selectivity over SIRT1 and 3, respectively. In vitro, these inhibitors are found to be toxic to lymphoma and epithelial cancer cell lines. In particular, compounds <b>55</b> (IC<sub>50</sub> SIRT2 0.25 µM and <25% inhibition at 50 µM against SIRT1 and SIRT3) and <b>56</b> (IC<sub>50</sub> SIRT2 0.78 µM and <25% inhibition at 50 µM against SIRT1 and SIRT3) showed apoptotic as well as strong anti-proliferative properties against B-cell lymphoma cells.https://www.mdpi.com/1420-3049/25/3/455sirtuinsirt2acetylationcancerlymphoma |
| spellingShingle | Sarwat Chowdhury Smitha Sripathy Alyssa A. Webster Angela Park Uyen Lao Joanne H. Hsu Taylor Loe Antonio Bedalov Julian A. Simon Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies Molecules sirtuin sirt2 acetylation cancer lymphoma |
| title | Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies |
| title_full | Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies |
| title_fullStr | Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies |
| title_full_unstemmed | Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies |
| title_short | Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies |
| title_sort | discovery of selective sirt2 inhibitors as therapeutic agents in b cell lymphoma and other malignancies |
| topic | sirtuin sirt2 acetylation cancer lymphoma |
| url | https://www.mdpi.com/1420-3049/25/3/455 |
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