In Vitro Phase I Cytochrome P450 Metabolism, Permeability and Pharmacokinetics of SB639, a Novel Histone Deacetylase Inhibitor in Preclinical Species

Paramesh, Venkatesh; Goh, Evelyn Mei Ling; Zeng, Peizi; New, Lee Sun; Liu, Xin; Pasha, Mohammad; Sangthongpitag, Kanda; Yeo, Pauline; Ethirajulu, Kantharaj

doi:10.1248/bpb.30.1021

Cited by 26 publications

(28 citation statements)

References 10 publications

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“…Although animal studies have showed that hydroxamate HDAC inhibitors such as vorinostat and panobinostat have low oral bioavailability and short half-life in plasma (30)(31)(32)(33), mouse pharmacokinetic studies show that CUDC-907 has an oral bioavailability approximately 2-fold higher than vorinostat and other HDAC inhibitors (Supplementary Fig. S8).…”

Section: Discussionmentioning

confidence: 99%

Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

Qian

Lai

Bao

et al. 2012

Clinical Cancer Research

195

176

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Purpose: Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells.Experimental Design: We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action.Results: CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells.Conclusions: CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks. Clin Cancer Res; 18(15); 4104-13. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

Qian

Lai

Bao

et al. 2012

Clinical Cancer Research

195

176

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“…It is well-known that hydroxamates such as vorinostat suffer from relatively short metabolic half-life owing to an easily reduced N−O bond, a hydrolytically labile amide linkage and the formation of glucoronides. 8,9 In contrast, the metal-targeting moiety of the tropolone can be viewed as an extended vinylogous carboxylic acid 8 and would not be subject to reductive or hydrolytic …”

mentioning

confidence: 99%

Tropolones As Lead-Like Natural Products: The Development of Potent and Selective Histone Deacetylase Inhibitors

Ononye

VanHeyst

Oblak

et al. 2013

ACS Med. Chem. Lett.

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Natural products have long been recognized as a rich source of potent therapeutics but further development is often limited by high structural complexity and high molecular weight. In contrast, at the core of the thujaplicins is a lead-like tropolone scaffold characterized by relatively low molecular weight, ample sites for diversification, and metal-binding functionality poised for targeting a range of metalloenzyme drug targets. Here, we describe the development of this underutilized scaffold for the discovery of tropolone derivatives that function as isozyme-selective inhibitors of the validated anticancer drug target, histone deacetylase (HDAC). Several monosubstituted tropolones display remarkable levels of selectivity for HDAC2 and potently inhibit the growth of T-cell lymphocyte cell lines. The tropolones represent a new chemotype of isozyme-selective HDAC inhibitors. KEYWORDS: Tropolone, HDAC, isozyme-selectivity, thujaplicin, metalloenzyme, T-lymphocyte cancer cell lines N atural products have long served as a rich source of drugs for a variety of indications ranging from anticancer to antimicrobial to neurological disorders. Typically these natural products are characterized by high molecular weight and potency as well as high levels of structural complexity with limited sites for diversification. In contrast, thujaplicins, members of the tropolone family of natural products, can be regarded as lead-like natural products. β-Thujaplicin (also known as hinokitiol) is characterized by low molecular weight (MW = 164) and a relatively lower level of complexity that allows more extensive structural modification. Thujaplicins are monoterpene natural products isolated from the heartwood of trees in the Cupressaceae family 1 that are associated with antiproliferative activity.2−4 There have been few attempts to utilize these lead-like compounds in drug discovery, perhaps exacerbated by limited synthetic accessibility to these nonbenzenoid aromatics.The tropolone functionality is uniquely disposed to strongly chelate metal ions, which may be a hallmark of the biological activity of these compounds.3 Substituted tropolones are a compelling and distinct chemotype for the development of inhibitors of metalloenzyme drug targets. Herein, we describe our efforts to use β-thujaplicin as a lead-like natural product to develop a novel class of inhibitors of histone deacetylase, a validated target in the treatment of cancer. 5,6 Of the 18 HDAC isoforms, 11 are metalloenzymes that use zinc to remove a terminal acetyl group from lysine residues present in histones and other client proteins. The reversible acetylation and hydrolysis of the ε-acetamide in histones is associated with regulation of gene expression. Interestingly, there are a variety of natural products that inhibit HDACs such as trichostatin A (TSA; Figure 1), romidepsin, and trapoxin. Both romidepsin and vorinostat were approved by the FDA for the treatment of cutaneous T-cell lymphoma; the latter possesses a zinc-targeting hydroxamate, similar to TS...

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“…Mean elimination half-life increased to 6.44-7.73 h compared to IV administration. The oral bioavailability of HS270 was estimated to be 7.3-15.5%, similar to SB639 (10.5%) [15], higher than that of the [15] and other HDAC inhibitors [16]. Antitumor activity of HS270 and this basic pharmacokinetic evaluation prompts us to believe that it is positive for further development of HS270 as an anticancer new drug.…”

Section: Parametersmentioning

confidence: 95%

“…The elimination half-life was found to be 2.17 ± 0.38 h. The mean total body clearance was 17.27 ± 3.93 L/h/kg and the volume of distribution at steady-state was 55.0 ± 20.4 L/kg. Table 6 also shows the pharmacokinetic parameters of other HDACis (SAHA, SB639) [15]. In comparison to SAHA and SB639, HS270 shows the highest elimination half-life.…”

Section: Preclinical Pharmacokinetic Studymentioning

confidence: 99%

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Determination of HS270, a new histone deacetylase inhibitor, in rat plasma by LC–MS/MS—Application to a preclinical pharmacokinetic study

Zhong

Chen

et al. 2011

Journal of Chromatography B

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In Vitro Phase I Cytochrome P450 Metabolism, Permeability and Pharmacokinetics of SB639, a Novel Histone Deacetylase Inhibitor in Preclinical Species

Cited by 26 publications

References 10 publications

Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

Tropolones As Lead-Like Natural Products: The Development of Potent and Selective Histone Deacetylase Inhibitors

Determination of HS270, a new histone deacetylase inhibitor, in rat plasma by LC–MS/MS—Application to a preclinical pharmacokinetic study

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