Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (1a), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (1s), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (1a). X-ray crystallography data reveal the molecular basis of HDAC6 inhibition by SW-101 (1s). Importantly, we demonstrate that SW-101 (1s) treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant MFN2. Taken together, these results bode well for the further development of SW-101 (1s) as a disease-modifying HDAC6i.

• MeSH
• acetylace MeSH
• benzamidy chemie   metabolismus   MeSH
• Charcotova-Marieova-Toothova nemoc farmakoterapie   metabolismus   patologie   MeSH
• chinoliny chemie   metabolismus   terapeutické užití   MeSH
• fenotyp MeSH
• histondeacetylasa 6 antagonisté a inhibitory   metabolismus   MeSH
• inhibitory histondeacetylas chemie   metabolismus   terapeutické užití   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• poločas MeSH
• protein - isoformy antagonisté a inhibitory   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• tubulin metabolismus   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Selective inhibition of histone deacetylase 6 (HDAC6) is being recognized as a therapeutic approach for cancers. In this study, we designed a new HDAC6 inhibitor, named Suprastat, using in silico simulations. X-ray crystallography and molecular dynamics simulations provide strong evidence to support the notion that the aminomethyl and hydroxyl groups in the capping group of Suprastat establish significant hydrogen bond interactions, either direct or water-mediated, with residues D460, N530, and S531, which play a vital role in regulating the deacetylase function of the enzyme and which are absent in other isoforms. In vitro characterization of Suprastat demonstrates subnanomolar HDAC6 inhibitory potency and a hundred- to a thousand-fold HDAC6 selectivity over the other HDAC isoforms. In vivo studies reveal that a combination of Suprastat and anti-PD1 immunotherapy enhances antitumor immune response, mediated by a decrease of protumoral M2 macrophages and increased infiltration of antitumor CD8+ effector and memory T-cells.

• MeSH
• fenylmočovinové sloučeniny chemická syntéza   metabolismus   terapeutické užití   MeSH
• histondeacetylasa 6 antagonisté a inhibitory   metabolismus   MeSH
• imunologické faktory chemická syntéza   metabolismus   terapeutické užití   MeSH
• imunoterapie MeSH
• inhibitory histondeacetylas chemická syntéza   metabolismus   terapeutické užití   MeSH
• jaterní mikrozomy metabolismus   MeSH
• krysa rodu rattus MeSH
• krystalografie rentgenová MeSH
• kyseliny hydroxamové chemická syntéza   metabolismus   terapeutické užití   MeSH
• lidé MeSH
• melanom farmakoterapie   terapie   MeSH
• myši inbrední C57BL MeSH
• nádorové buněčné linie MeSH
• racionální návrh léčiv MeSH
• simulace molekulární dynamiky MeSH
• vazba proteinů MeSH
• vodíková vazba MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Tubastatin A, a tetrahydro-γ-carboline-capped selective HDAC6 inhibitor (HDAC6i), was rationally designed 10 years ago, and has become the best investigated HDAC6i to date. It shows efficacy in various neurological disease animal models, as HDAC6 plays a crucial regulatory role in axonal transport deficits, protein aggregation, as well as oxidative stress. In this work, we provide new insights into this HDAC6i by investigating the molecular basis of its interactions with HDAC6 through X-ray crystallography, determining its functional capability to elevate the levels of acetylated α-tubulin in vitro and in vivo, correlating PK/PD profiles to determine effective doses in plasma and brain, and finally assessing its therapeutic potential toward psychiatric diseases through use of the SmartCube screening platform.

• Publikační typ
• časopisecké články MeSH

Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1-/- mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC50 = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the α-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates α-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated α-tubulin levels in the hippocampus of Fmr1-/- mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1-/- mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease.

• MeSH
• benzamidy farmakologie   MeSH
• chinoliny farmakologie   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• histondeacetylasa 6 antagonisté a inhibitory   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• kognice účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• paměť účinky léků   MeSH
• posttranslační úpravy proteinů účinky léků   MeSH
• syndrom fragilního X enzymologie   patofyziologie   MeSH
• učení účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.

• MeSH
• CD8-pozitivní T-lymfocyty cytologie   MeSH
• dánio pruhované MeSH
• histondeacetylasa 6 antagonisté a inhibitory   MeSH
• inhibitory histondeacetylas chemie   farmakologie   MeSH
• isoxazoly chemie   farmakologie   MeSH
• katalytická doména MeSH
• kyseliny hydroxamové chemie   farmakologie   MeSH
• lidé MeSH
• makrofágy cytologie   MeSH
• melanom farmakoterapie   MeSH
• mikrozomy chemie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• NKT buňky cytologie   MeSH
• objevování léků MeSH
• transplantace izogenní MeSH
• zinek chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Mercaptoacetamide histone deacetylase inhibitors are neuroprotective agents that do not exhibit the genotoxicity associated with more commonly used hydroxamate inhibitors. Here, we present the crystal structure of a selective mercaptoacetamide complexed with the C-terminal catalytic domain of HDAC6. When compared with the structure of a mercaptoacetamide bound to the class I isozyme HDAC8, different interactions are observed with the conserved tandem histidine pair in the active site. These differences likely contribute to the selectivity for inhibition of HDAC6, an important target for cancer chemotherapy and the treatment of neurodegenerative disease.

• Publikační typ
• časopisecké články MeSH

The design and synthesis of prostate specific membrane antigen (PSMA) ligands derived from 2-aminoadipic acid, a building block that has not previously been used to construct PSMA ligands, are reported. The effects of both the linker length and of an N-substituent of our PSMA ligands were probed, and X-ray structures of five of these ligands bound to PSMA were obtained. Among the ligands disclosed herein, 13b showed the highest inhibitory activity for PSMA. As ligand 13b can readily be radiolabeled since its fluorine atom is adjacent to the nitrogen atom of its pyridine ring, the use of this and related compounds as theranostics can be pursued.

• Publikační typ
• časopisecké články MeSH

Only a handful of therapies offer significant improvement in the overall survival in cases of melanoma, a cancer whose incidence has continued to rise in the past 30 years. In our effort to identify potent and isoform-selective histone deacetylase (HDAC) inhibitors as a therapeutic approach to melanoma, a series of new HDAC6 inhibitors based on the nexturastat A scaffold were prepared. The new analogues 4d, 4e, and 7b bearing added hydrophilic substituents, so as to establish additional hydrogen bonding on the rim of the HDAC6 catalytic pocket, exhibit improved potency against HDAC6 and retain selectivity over HDAC1. Compound 4d exhibits antiproliferative effects on several types of melanoma and lymphoma cells. Further studies indicates that 4d selectively increases acetylated tubulin levels in vitro and elicits an immune response through down-regulating cytokine IL-10. A preliminary in vivo efficacy study indicates that 4d possesses improved capability to inhibit melanoma tumor growth and that this effect is based on the regulation of inflammatory and immune responses.

• Publikační typ
• časopisecké články MeSH

A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC50, 11 and 2.8 nM) and excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concentration of 7e and 13a upon microsomal incubation. Administration of 15 and 16in vivo was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.

• Publikační typ
• časopisecké články MeSH