Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models
- Satish NoonepalleSatish NoonepalleDepartment of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia 20052, United StatesMore by Satish Noonepalle
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- Sida ShenSida ShenDepartment of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United StatesMore by Sida Shen
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- Jakub PtáčekJakub PtáčekLaboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, Vestec 252 50, Czech RepublicMore by Jakub Ptáček
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- Maurício T. TavaresMaurício T. TavaresDepartment of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United StatesMore by Maurício T. Tavares
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- Guiping ZhangGuiping ZhangDepartment of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United StatesMore by Guiping Zhang
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- Jan StránskýJan StránskýCentre of Molecular Structure, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, Vestec 252 50, Czech RepublicMore by Jan Stránský
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- Jiří PavlíčekJiří PavlíčekCentre of Molecular Structure, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, Vestec 252 50, Czech RepublicMore by Jiří Pavlíček
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- Glaucio M. FerreiraGlaucio M. FerreiraDepartment of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP 05508-000, BrazilMore by Glaucio M. Ferreira
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- Melissa HadleyMelissa HadleyDepartment of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia 20052, United StatesMore by Melissa Hadley
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- Guido PelaezGuido PelaezDepartment of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia 20052, United StatesMore by Guido Pelaez
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- Cyril Bařinka*Cyril Bařinka*Email: [email protected]. Phone: +420-325-873-777.Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, Vestec 252 50, Czech RepublicMore by Cyril Bařinka
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- Alan P. Kozikowski*Alan P. Kozikowski*Email: [email protected]. Phone: +1-773-793-5866.Bright Minds Biosciences, Toronto, ON M5H 3V9, CanadaMore by Alan P. Kozikowski
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- Alejandro Villagra*Alejandro Villagra*Email: [email protected]. Phone: +1-202-994-9547.Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia 20052, United StatesMore by Alejandro Villagra
Abstract
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.
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