Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
Add more filters










Database
Language
Publication year range
1.
EMBO Rep ; 24(5): e56052, 2023 05 04.
Article in English | MEDLINE | ID: mdl-36896611

ABSTRACT

Lysine lactylation (Kla) is a recently discovered histone mark derived from metabolic lactate. The NAD+ -dependent deacetylase SIRT3, which can also catalyze removal of the lactyl moiety from lysine, is expressed at low levels in hepatocellular carcinoma (HCC) and has been suggested to be an HCC tumor suppressor. Here we report that SIRT3 can delactylate non-histone proteins and suppress HCC development. Using SILAC-based quantitative proteomics, we identify cyclin E2 (CCNE2) as one of the lactylated substrates of SIRT3 in HCC cells. Furthermore, our crystallographic study elucidates the mechanism of CCNE2 K348la delactylation by SIRT3. Our results further suggest that lactylated CCNE2 promotes HCC cell growth, while SIRT3 activation by Honokiol induces HCC cell apoptosis and prevents HCC outgrowth in vivo by regulating Kla levels of CCNE2. Together, our results establish a physiological function of SIRT3 as a delactylase that is important for suppressing HCC, and our structural data could be useful for the future design of activators.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Sirtuin 3 , Humans , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Sirtuin 3/genetics , Sirtuin 3/metabolism , Lysine , Cell Proliferation , Cyclins/genetics
2.
ACS Chem Biol ; 16(12): 2746-2751, 2021 12 17.
Article in English | MEDLINE | ID: mdl-34860497

ABSTRACT

Histone deacetylase 6 (HDAC6) is a potential therapeutic target for treating several diseases. A recent study revealed that HDAC6 is important for NLRP3 inflammasome activation, suggesting that targeting HDAC6 could be useful for treating many inflammatory disorders. Using the proteolysis targeting chimera (PROTAC) strategy, we herein report an HDAC6 degrader with low cytotoxicity by tethering a selective HDAC6 inhibitor derived from a natural product, indirubin, with pomalidomide, a CRBN E3 ligand. Our HDAC6 degrader efficiently and selectively decreased HDAC6 levels in several cell lines, including activated THP-1 cells. Application of this HDAC6 degrader attenuated NLRP3 inflammasome activation in LPS-induced mice, which for the first time demonstrates that HDAC6 PROTAC could be a novel strategy to treat NLRP3 inflammasome-associated diseases.


Subject(s)
Histone Deacetylase 6 , Histone Deacetylase Inhibitors , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , Humans , Drug Development , HeLa Cells , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/chemistry , Indoles/chemistry , Inflammasomes/chemistry , K562 Cells , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Proteolysis , Structure-Activity Relationship , Thalidomide/analogs & derivatives
3.
J Med Chem ; 64(20): 15280-15296, 2021 10 28.
Article in English | MEDLINE | ID: mdl-34624191

ABSTRACT

To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound 8b with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC50 = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in several cancer cell lines. In particular, compound 8b can prevent the proliferation of a non-small-cell lung cancer cell line (A549) through the Mcl-1/XIAP/PARP axis, in agreement with the unique modes of action of the combined agents of HDAC inhibitors and CDK inhibitors. In an A549 xerograph model, compound 8b showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound 8b as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.


Subject(s)
Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Histone Deacetylases/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Cyclin-Dependent Kinases/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Structure-Activity Relationship , Tumor Cells, Cultured
4.
Eur J Med Chem ; 225: 113799, 2021 Dec 05.
Article in English | MEDLINE | ID: mdl-34500130

ABSTRACT

Zinc-dependent histone deacetylases (HDACs) are important epigenetic regulators that have become important drug targets for treating cancer. Although five HDAC inhibitors have been approved for treating several cancers, there is still a huge demand on discovering new HDAC inhibitors to explore the therapeutic potentials for treating solid tumor cancers. Substrate mimics are a powerful rational design approach for the development of potent inhibitors. Here we describe the rational design, synthesis, biological evaluation, molecular docking and in vivo efficacy study of a class of HDAC inhibitors using Nε-acetyl lysine mimics that are derived from cysteine. As a result, compounds 7a, 9b and 13d demonstrated pan-HDAC inhibition and broad cytotoxicity against several cancer cell lines, comparable to the approved HDAC inhibitor SAHA. Furthermore, 13d significantly inhibited tumor growth in a A549 xenograft mice model without any obvious weight loss, supporting that the cysteine-derived acetyl lysine mimics are promising HDAC inhibitors with therapeutic potentials for treating cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Cysteine/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Lysine/pharmacology , Zinc/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cysteine/chemical synthesis , Cysteine/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Lysine/chemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Docking Simulation , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Structure-Activity Relationship
5.
RSC Adv ; 11(5): 2677-2681, 2021 Jan 11.
Article in English | MEDLINE | ID: mdl-35747080

ABSTRACT

SIRT4 belongs to one of three mitochondrial sirtuins, which plays important roles in regulating many biological processes and has significant implications for treating several human diseases. However, the development of those small compounds that can modulate SIRT4 activities is limited because there is no efficient SIRT4 assay available for screening its modulators. Thanks to recent discoveries of several enzymatic activities and substrates for SIRT4, we have developed a FRET-based assay suitable for screening SIRT4 modulators based on its activity of removing 3-hydroxy-3-methylglutaryl (HMG) lysine modification, which could be further coupled with a secondary FRET-based assay for other sirtuins to identify SIRT4-specific inhibitors or activators.

6.
Chem Pharm Bull (Tokyo) ; 68(7): 613-617, 2020.
Article in English | MEDLINE | ID: mdl-32611998

ABSTRACT

Although anthraquinone derivatives possess significant antitumor activity, most of them also displayed those side effects like cardiotoxicity, mainly owing to their inhibition of topoisomerase II of DNA repair mechanisms. Our raised design strategy by switching therapeutic target from topoisomerase II to histone deacetylase (HDAC) has been applied to the design of anthraquinone derivatives in current study. Consequently, a series of novel HDAC inhibitors with a tricylic diketone of anthraquinone as a cap group have been synthesized. After screening and evaluation, compounds 4b, 4d, 7b and 7d have displayed the comparable inhibition in enzymatic activity and cell proliferation than that of Vorinostat (SAHA). Notably, compound 4b showed certain selectivity of antiproliferative effects on cancer cell lines over non-cancer cell lines.


Subject(s)
Anthraquinones/pharmacology , DNA Topoisomerases, Type II/metabolism , Histone Deacetylase Inhibitors/pharmacology , Anthraquinones/chemical synthesis , Anthraquinones/chemistry , Cell Line , Cell Proliferation/drug effects , DNA Repair , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship
7.
Bioorg Med Chem ; 28(6): 115353, 2020 03 15.
Article in English | MEDLINE | ID: mdl-32061485

ABSTRACT

A series of sirtuin inhibitor candidates were assembled based on an intermediate ester (1a) our accidently discovered. After screening and evaluation, several SIRT2 selective inhibitors were identified, which can inhibit all the deacetylation, defatty-acylation and debenzoylation of SIRT2. Among these inhibitors, compound 1e was the best SIRT2 selective inhibitors. The primary study on the inhibitory mechanism indicated that compound 1e may be a suicide inhibitor acting as an irreversible way. Given almost all reported sirtuin inhibitors are non-covalent, sirtuin covalent inhibitors are still need to be developed. These findings will facilitate for further development of SIRT2 selective and suicide inhibitors.


Subject(s)
Enzyme Inhibitors/pharmacology , Sirtuin 2/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Sirtuin 2/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...