Photocaged Histone Deacetylase Inhibitors as Prodrugs in Targeted Cancer Therapy

Kraft, Fabian B.; Hanl, Maria; Feller, Felix; Schäker-Hübner, Linda; Hansen, Finn K.

doi:10.3390/ph16030356

Cited by 9 publications

(2 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The enzyme and inhibitor were preincubated at 25 °C for 60 min. Afterward, the fluorogenic substrate ZMAL (Z-Lys(Ac)-AMC; 68 10 μL; 75 μM in assay buffer) was added. In the case of HDAC4, the fluorogenic substrate Boc-Lys(Tfa)-AMC (Bachem, Catalog no.…”

Section: -[2-(benzylamino)-2-oxoethyl]-n-{4-[5-(difluoromethyl)-134ox...mentioning

confidence: 99%

Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase 6

König,

Watson,

Reßing

et al. 2023

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Histone deacetylase 6 (HDAC6) is an important drug target in oncological and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize hydroxamic acids as a zinc-binding group, which limits therapeutic opportunities due to its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO 6 is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp2 carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally result in an essentially irreversible inhibition of HDAC6.

show abstract

Section: -[2-(benzylamino)-2-oxoethyl]-n-{4-[5-(difluoromethyl)-134ox...mentioning

confidence: 99%

Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase 6

König,

Watson,

Reßing

et al. 2023

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…First, all synthesized hydroxamic acids were evaluated in biochemical HDAC inhibition assays for their inhibitory activity against human HDAC1 and HDAC6 isoforms using ZMAL as substrate. 36 The results are summarized in Table 1. 34 We started the structural modification on the side chain R 1 of the cap group to improve the interaction with the L1-loop.…”

Section: Inhibitory Activity Against Human Hdac Isoformsmentioning

confidence: 99%

Groebke Blackburn Bienaymé-mediated multi-component synthesis of selective HDAC6 inhibitors with anti-inflammatory properties

Kraft,

Enns,

Honin

et al. 2023

Preprint

View full text Add to dashboard Cite

Histone deacetylases (HDACs) are a class of enzymes that cleave acyl groups from lysine residues of histone and non-histone proteins. There are 18 human HDAC isoforms with different cellular targets and functions. Among them, HDAC6 was found to be overexpressed in different types of cancer. However, when used in monotherapy, HDAC6 inhibition by selective inhibitors fails to show pronounced anti-cancer effects. The HDAC6 enzyme also addresses non-histone proteins like tubulin and cortactin, making it important for cell migration and angiogenesis. Recently, the NLRP3 inflammasome was identified as an important regulator of inflammation and immune responses and, importantly, HDAC6 is critically involved the activation of the inflammasome. We herein report the design, synthesis and biological evaluation of a library of selective HDAC6 inhibitors. Starting from the previously published crystal structure of MAIP-032 in complex with CD2 of zHDAC6, we performed docking studies to evaluate additional possible interactions of the cap group with the L1-loop pocket. Based on the results we synthesized 13 novel HDAC6 inhibitors via the Groebke Blackburn Bienaymé three component reaction as the key step. Compound 8k and 8m emerged as the most potent and selective inhibitors of HDAC6. Subsequent immunoblot analysis confirmed the high selectivity of 8k and 8m for HDAC6 in a cellular environment. While neither 8k and 8m nor the selectivity HDAC6 inhibitor tubastatin A showed antiproliferative effects in the U 87 MG glioblastoma cell line, compound 8m attenuated cell migration significantly in wound healing assays in U-87 MG cells. Moreover, in macrophages compounds 8k and 8m demonstrated significant inhibition of LPS-induced IL1B mRNA expression and TNF release. These findings suggest that our imidazo[1,2-a]pyridine-capped HDAC6 inhibitors may serve as promising candidates for the development of drugs to effectively treat NLRP3 inflammasome-driven inflammatory diseases.

show abstract

Micro-scale screening of genetically modified Fusarium fujikuroi strain extends the apicidin family

Fischle,

Lutsch,

Hübner

et al. 2024

Nat. Prod. Bioprospect.

View full text Add to dashboard Cite

Apicidins are a class of naturally occurring cyclic tetrapeptides produced by few strains within the Fusarium genus. These secondary metabolites have gained significant attention due to their antiprotozoal activity through HDAC inhibition, thereby highlighting their potential for the treatment of malaria. Predominantly, apicidins have been isolated from Fusarium semitectum, offering a deep insight into the biosynthetic pathway responsible for their formation. A similar biosynthetic gene cluster has also been identified in the rice pathogenic fungus F. fujikuroi, leading the discovery of three additional apicidins through genetic manipulation. Routine mass spectrometric screening of these compound-producing strains revealed another metabolite structurally related to previously studied apicidins. By optimizing culture conditions and developing an effective isolation method, we obtained a highly pure substance, whose chemical structure was fully elucidated using NMR and HRMS fragmentation. Further studies were conducted to determine cytotoxicity, antimalarial activity, and HDAC inhibitory activity of this new secondary metabolite alongside the previously known apicidins. This work not only expands the apicidin class with a new member but also provides extensive insights and comparative analysis of apicidin-like substances produced by F. fujikuroi. Graphical Abstract

show abstract

Photocaged Histone Deacetylase Inhibitors as Prodrugs in Targeted Cancer Therapy

Cited by 9 publications

References 36 publications

Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase 6

Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase 6

Groebke Blackburn Bienaymé-mediated multi-component synthesis of selective HDAC6 inhibitors with anti-inflammatory properties

Micro-scale screening of genetically modified Fusarium fujikuroi strain extends the apicidin family

Contact Info

Product

Resources

About