1. A Small-Molecule SIRT2 Inhibitor That Promotes K-Ras4a Lysine Fatty-Acylation
Hui Jing, Hening Lin, Miao Wang, Xiaoyu Zhang, Min Yang, Jun Young Hong, Jing Hu, Ji Cao, Ian R Price, Nicole A Spiegelman ChemMedChem . 2019 Apr 3;14(7):744-748. doi: 10.1002/cmdc.201800715.
SIRT2, a member of the sirtuin family of protein lysine deacylases, has been identified as a promising therapeutic target for treating cancer. In addition to catalyzing deacetylation, SIRT2 has recently been shown to remove fatty acyl groups from K-Ras4a and promote its transforming activity. Among the SIRT2-specific inhibitors, only the thiomyristoyl lysine compound TM can weakly inhibit the demyristoylation activity of SIRT2. Therefore, more potent small-molecule SIRT2 inhibitors are needed to further evaluate the therapeutic potential of SIRT2 inhibition, and to understand the function of protein lysine defatty-acylation. Herein we report a SIRT2 inhibitor, JH-T4, which can increase K-Ras4a lysine fatty acylation. This is the first small-molecule inhibitor that can modulate the lysine fatty acylation levels of K-Ras4a. JH-T4 also inhibits SIRT1 and SIRT3 in vitro. The increased potency of JH-T4 is likely due to the formation of hydrogen bonding between the hydroxy group and SIRT1, SIRT2, and SIRT3. This is further supported by in vitro studies with another small-molecule inhibitor, NH-TM. These studies provide useful insight for future SIRT2 inhibitor development.
2. A Glycoconjugated SIRT2 Inhibitor with Aqueous Solubility Allows Structure-Based Design of SIRT2 Inhibitors
Jun Young Hong, Hening Lin, Jessica Jingyi Bai, Ian Robert Price ACS Chem Biol . 2019 Aug 16;14(8):1802-1810. doi: 10.1021/acschembio.9b00384.
Small molecule inhibitors for SIRT2, a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent protein lysine deacylases, have shown promise in treating cancer and neurodegenerative diseases. Developing SIRT2-selective inhibitors with better pharmacological properties is key to further realize the therapeutic potential of targeting SIRT2. One of the best SIRT2-selective inhibitors reported is a thiomyristoyl lysine compound called TM, which showed promising anticancer activity in mouse models without much toxicity to normal cells. The main limitations of TM, however, are the low aqueous solubility and lack of X-ray crystal structures to aid future drug design. Here, we designed and synthesized a glucose-conjugated TM (glucose-TM) analog with superior aqueous solubility. Although glucose-TM is not cell permeable, the excellent aqueous solubility allowed us to obtain a crystal structure of SIRT2 in complex with it. The structure enabled us to design several new TM analogs, one of which, NH4-6, showed superior water solubility and better anticancer activity in cell culture. The results of these studies provided important insights that will further fuel the future development of improved SIRT2 inhibitors as promising therapeutics for treating cancer and neurodegeneration.
3. Thiomyristoyl peptides as cell-permeable Sirt6 inhibitors
Bin He, Hening Lin, Jing Hu, Xiaoyu Zhang Org Biomol Chem . 2014 Oct 14;12(38):7498-502. doi: 10.1039/c4ob00860j.
Sirtuins regulate a variety of biological pathways and inhibitors of sirtuins have been actively pursued as tool compounds to study sirtuin biology and as potential therapeutics. Here we demonstrate that thiomyristoyl peptides are potent and cell-permeable inhibitors of Sirt6, one of the seven human sirtuins, and will serve as the starting point for the development of more specific Sirt6 inhibitors.
