Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase.

Kijima, Masako; Yoshida, Minoru; Sakai, Kenji; Horinouchi, Sueharu; Beppu, Teruhiko

doi:10.1016/s0021-9258(18)41547-5

Cited by 487 publications

(131 citation statements)

References 27 publications

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“…Through their actions on histones and other non-histone proteins HDACs serve as important regulators of a variety of cellular processes including proliferation, differentiation, cell survival, and cell death (1)(2)(3)(4). Moreover, deregulated functioning of HDACs has been implicated in serious pathologies such as cancer and neurodegenerative disease (5,6).…”

Section: Introductionmentioning

confidence: 99%

Polydactyly in Mice Lacking HDAC9/HDRP

Morrison

D’Mello

2008

Exp Biol Med (Maywood)

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Mice lacking histone deacetylase 9 (HDAC9) and its truncated variant, HDRP, exhibit post-axial polydactyly that manifests as an extra big toe on the right hind foot. Polydactyly in HDAC9/ HDRP knockout mice occurs with incomplete penetrance and affects both genders similarly. Because polydactyly can result from overactivity of sonic hedgehog (Shh) signaling, we investigated whether HDRP acted as a negative regulator of the Shh pathway. We find that Gli1, a transcription factor and downstream mediator of Shh signaling, is expressed at substantially higher levels in the feet of perinatal HDAC9/ HDRP-/- mice as compared with wild-type littermates. To more directly examine whether HDRP negatively-regulates Shh signaling we utilized cell lines that express components of the Shh pathway and that respond to the Shh agonist purmorphamine. We find that purmorphamine-mediated stimulation of Gli1 in the NIH 3T3 and HT22 cell lines is inhibited by the expression of HDRP. In HT22 cells, purmorphamine treatment leads to an increase in the rate of cell proliferation, which is also inhibited by HDRP. This inhibitory effect of HDRP on purmorphamine-mediated cell proliferation was also observed in primary cultures of glial cells. Although the mechanism by which it inhibits Gli1 induction and cell proliferation by purmorphamine is not clear, HDRP localizes to the nucleus suggesting it acts just upstream of Gli3 activation in the signaling cascade activated by Shh. Taken together our results suggest that HDRP acts as a negative regulator of the Shh pathway and that the absence of HDRP results in hyper-activation of this pathway resulting in polydactyly.

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Section: Introductionmentioning

confidence: 99%

Polydactyly in Mice Lacking HDAC9/HDRP

Morrison

D’Mello

2008

Exp Biol Med (Maywood)

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“…[2] Sequence homology indicates that the class-1 HDACs are having conserved residues for the ion binding, also closely resemble with other HDAC families. [11] In the past three decades, a number of HDAC inhibitors (HDACis) have been reported both naturally occurring such as trichostatin A (TSA), [12] apicidin, [13] trapoxin (TPX), [14] FK-228 (romidepsin), [15] and synthetic molecules such as SAHA, [16] cyclic hydroxamic-acid-containing peptides (CHAPs), [17] etc. (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…In the past three decades, a number of HDAC inhibitors (HDACis) have been reported both naturally occurring such as trichostatin A (TSA), [12] apicidin, [13] trapoxin (TPX), [14] FK‐228 (romidepsin), [15] and synthetic molecules such as SAHA, [16] cyclic hydroxamic‐acid‐containing peptides (CHAPs), [17] etc. (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Conformational Studies of Cyclic Tetrapeptides having βγ Fused Turns as HDAC Inhibitors

et al. 2021

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Histone deacetylases (HDACs) belong to a class of major targets for the development of anticancer drugs for which cyclic peptide-based molecules are attracting wide attention. Here we show the synthesis, conformational and in silico analysis of tetrahydrofuran amino acid (TAA) based 15-membered cyclic tetrapeptides (CTPs) containing hydroxamic acid side chain as potential HDAC inhibitors. NMR based solution studies in protected and deprotected forms reveal that the macrocycles are stabilized by 10-membered β-turn as well as a 7-membered γ-turn. This type of fused structures within the same macrocycle is not frequently sighted. Our initial in silico docking results indicated that the hydroxamic acid protected CTPs show promising binding with the class-1 HDACs. We also noticed that the C-chain with hydroxamic functional group attached on the ornithine sidechain did not affect the core structure of the peptide ring. Moreover, some of these cyclic tetrapeptides with hydroxamic acid side chain exhibited an induction of acetylation of histones on preliminary cell-based experiments. Our initial results provide an insight into the development of HDAC inhibitors based on the CTPs with novel βγ fused turns which have not been explored yet.

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“…For over three decades, HDACs have been targeted for various cancer treatments which have resulted in the approval of five HDAC inhibitors with several others in clinical trials for the treatment of several types of cancer [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. Most of the designed, developed and reported HDAC inhibitors have a general structural pharmacophore consisting of three features—the zinc-binding group (ZBG), the linker and the capping group (cap) [ 39 , 40 , 41 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors

et al. 2021

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Histone-modifying proteins have been identified as promising targets to treat several diseases including cancer and parasitic ailments. In silico methods have been incorporated within a variety of drug discovery programs to facilitate the identification and development of novel lead compounds. In this study, we explore the binding modes of a series of benzhydroxamates derivatives developed as histone deacetylase inhibitors of Schistosoma mansoni histone deacetylase (smHDAC) using molecular docking and binding free energy (BFE) calculations. The developed docking protocol was able to correctly reproduce the experimentally established binding modes of resolved smHDAC8–inhibitor complexes. However, as has been reported in former studies, the obtained docking scores weakly correlate with the experimentally determined activity of the studied inhibitors. Thus, the obtained docking poses were refined and rescored using the Amber software. From the computed protein–inhibitor BFE, different quantitative structure–activity relationship (QSAR) models could be developed and validated using several cross-validation techniques. Some of the generated QSAR models with good correlation could explain up to ~73% variance in activity within the studied training set molecules. The best performing models were subsequently tested on an external test set of newly designed and synthesized analogs. In vitro testing showed a good correlation between the predicted and experimentally observed IC50 values. Thus, the generated models can be considered as interesting tools for the identification of novel smHDAC8 inhibitors.

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Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase.

Cited by 487 publications

References 27 publications

Polydactyly in Mice Lacking HDAC9/HDRP

Polydactyly in Mice Lacking HDAC9/HDRP

Design, Synthesis and Conformational Studies of Cyclic Tetrapeptides having βγ Fused Turns as HDAC Inhibitors

Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors

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