A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity

Jing, Hui; Hu, Jing; He, Bin; Abril, Yashira L. Negrón; Stupinski, Jack; Weiser, Keren; Carbonaro, Marisa; Chiang, Ying-Ling; Southard, Teresa; Giannakakou, Paraskevi; Weiss, Robert S.; Lin, Hening

doi:10.1016/j.ccell.2016.04.005

Cited by 124 publications

(118 citation statements)

References 58 publications

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“…We previously developed a potent SIRT2-specific thiomyristoyl (TM) inhibitor and also obtained a structure of SIRT2 in complex with a thiomyristoyl peptide (PKK(TMy)TG), referred to as BHJH-TM1 in Teng et al (Jing, et al, 2016; Teng, et al, 2015). To obtain more information about the catalytic mechanism, we soaked the SIRT2/BHJH-TM1 crystals with carba-NAD or NAD to get potential catalytic intermediates.…”

Section: Resultsmentioning

confidence: 99%

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Deacylation Mechanism by SIRT2 Revealed in the 1′-SH-2′-O-Myristoyl Intermediate Structure

Wang

Fung

Zhang

et al. 2017

Cell Chemical Biology

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Summary Sirtuins are NAD-dependent deacylases. Previous studies have established two important enzymatic intermediates in sirtuin-catalyzed deacylation, an alkylamidate intermediate I, which is then converted to a bicyclic intermediate II. However, how intermediate II is converted to products is unknown. Based on potent SIRT2-specific inhibitors we developed, here we report crystal structures of SIRT2 in complexes with a thiomyristoyl (TM) inhibitor and carba-NAD or NAD. Interestingly by soaking crystals with NAD, we capture a distinct covalent catalytic intermediate (III) that is different from the intermediates I and II. In this intermediate, the covalent bond between the S and the myristoyl carbonyl carbon is broken and we believe this intermediate III is the decomposition product of II in route to form the end products. MALDI-TOF data further support the intermediate III formation. This is the first time such an intermediate is captured by X-ray crystallography and provides more mechanistic insights into sirtuin-catalyzed reactions.

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Section: Resultsmentioning

confidence: 99%

“…Synthesis of Peptides of BHJH-TM1 is as reported protocol (Jing, et al, 2016). Thiomyristoyl peptides1 was synthesized using standard Fmoc/tBu chemistry O-benzotriazol-N,N,N′,N′-tetramethyluronium hexafluorophosphate/1-hydroxybenzotriazol (HBTU/HOBt) protocol with Wang resin.…”

Section: Methodsmentioning

confidence: 99%

Deacylation Mechanism by SIRT2 Revealed in the 1′-SH-2′-O-Myristoyl Intermediate Structure

Wang

Fung

Zhang

et al. 2017

Cell Chemical Biology

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“…Several SIRT2 inhibitors have been developed . Recent studies suggest that among these compounds, only TM can weakly inhibit the demyristoylation activity of SIRT2 .…”

Section: Figurementioning

confidence: 99%

“…Recent studies suggest that among these compounds, only TM can weakly inhibit the demyristoylation activity of SIRT2 . TM is a thiomyristoyl lysine compound, and is a mechanism‐based SIRT2 inhibitor . TM has been shown to possess a broad anticancer effect .…”

Section: Figurementioning

confidence: 99%

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A Small‐Molecule SIRT2 Inhibitor That Promotes K‐Ras4a Lysine Fatty‐Acylation

Spiegelman

Hong

et al. 2019

ChemMedChem

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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.

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Promotion of Lung Cancer Metastasis by SIRT2‐Mediated Extracellular Protein Deacetylation

Xiong

Zhao

et al. 2022

Advanced Science

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Acetylation of extracellular proteins has been observed in many independent studies where particular attention has been given to the dynamic change of the microenvironmental protein post‐translational modifications. While extracellular proteins can be acetylated within the cells prior to their micro‐environmental distribution, their deacetylation in a tumor microenvironment remains elusive. Here it is described that multiple acetyl‐vWA domain‐carrying proteins including integrin β 3 (ITGB3) and collagen 6A (COL6A) are deacetylated by Sirtuin family member SIRT2 in extracellular space. SIRT2 is secreted by macrophages following toll‐like receptor (TLR) family member TLR4 or TLR2 activation. TLR‐activated SIRT2 undergoes autophagosome translocation. TNF receptor associated factor 6 (TRAF6)‐mediated autophagy flux in response to TLR2/4 activation can then pump SIRT2 into the microenvironment to function as extracellular SIRT2 (eSIRT2). In the extracellular space, eSIRT2 deacetylates ITGB3 on aK416 involved in cell attachment and migration, leading to a promotion of cancer cell metastasis. In lung cancer patients, significantly increased serum eSIRT2 level correlates with dramatically decreased ITGB3‐K416 acetylation in cancer cells. Thus, the extracellular space is a subcellular organelle‐like arena where eSIRT2 promotes cancer cell metastasis via catalyzing extracellular protein deacetylation.

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A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity

Cited by 124 publications

References 58 publications

Deacylation Mechanism by SIRT2 Revealed in the 1′-SH-2′-O-Myristoyl Intermediate Structure

Deacylation Mechanism by SIRT2 Revealed in the 1′-SH-2′-O-Myristoyl Intermediate Structure

A Small‐Molecule SIRT2 Inhibitor That Promotes K‐Ras4a Lysine Fatty‐Acylation

Promotion of Lung Cancer Metastasis by SIRT2‐Mediated Extracellular Protein Deacetylation

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