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Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models

S. Noonepalle, S. Shen, J. Ptáček, MT. Tavares, G. Zhang, J. Stránský, J. Pavlíček, GM. Ferreira, M. Hadley, G. Pelaez, C. Bařinka, AP. Kozikowski, A. Villagra

. 2020 ; 63 (18) : 10246-10262. [pub] 20200902

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21012123

Grantová podpora
R21 CA184612 NCI NIH HHS - United States
R01 NS079183 NINDS NIH HHS - United States
R43 HD093464 NICHD NIH HHS - United States
R41 AG058283 NIA NIH HHS - United States

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.

Citace poskytuje Crossref.org

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