title: Potent and Selective Non-hydroxamate Histone Deacetylase 8 Inhibitors.
abstract: Specific inhibition of histone deacetylase 8 (HDAC8) has been suggested as a promising option for the treatment of neuroblastoma and T-cell malignancies. A novel class of highly potent and selective HDAC8 inhibitors with a pyrimido[1,2-c][1,3]benzothiazin-6-imine scaffold was studied that is completely different from the traditional concept of HDAC inhibitors comprising a zinc binding group (ZBG), in most cases a hydroxamate group, a spacer, and a capping group that may interact with the surface of the target protein. Although lacking a ZBG, some of the new compounds were shown to have outstanding potency against HDAC8 in the single-digit nanomolar range. The pyrimido[1,2-c][1,3]benzothiazin-6-imines also inhibited the growth of solid and hematological tumor cells. The small size and beneficial physicochemical properties of the novel HDAC inhibitor class underline the high degree of drug likeness. This and the broad structure-activity relationship suggest great potential for the further development of compounds with the pyrimido[1,2-c][1,3]benzothiazin-6-imine scaffold into innovative and highly effective therapeutic drugs against cancer.
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Schnittspahnstr. 12, 64287, Darmstadt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kleinschek
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Schnittspahnstr. 12, 64287, Darmstadt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Meyners
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche, MATI Center of Excellence, Università degli Studi di Udine, P.le Kolbe 4, 33100, Udine, Italy.
authors.forename: Eros
authors.initials: E
authors.lastname: Digiorgio
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche, MATI Center of Excellence, Università degli Studi di Udine, P.le Kolbe 4, 33100, Udine, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Brancolini
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Schnittspahnstr. 12, 64287, Darmstadt, Germany.
authors.forename: Franz-Josef
authors.identifier: http://orcid.org/0000-0002-1001-3249
authors.initials: FJ
authors.lastname: Meyer-Almes
mesh_terms: D000107:Acetylation; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D055808:Drug Discovery; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D007097:Imines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019169:Jurkat Cells; D061986:MCF-7 Cells; D025341:Principal Component Analysis; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002868:Chromosomal Proteins, Non-Histone; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007097:Imines; D020033:Protein Isoforms; D011743:Pyrimidines; D012097:Repressor Proteins; C492318:SMC3 protein, human; C579456:pyrimido(1,2-c)(1,3)benzothiazin-6-imine; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: HDAC8; cancer; drug discovery; histone deacetylase 8; inhibitors