Biocatalytic Synthesis and Structure Elucidation of Cyclized Metabolites of the Deacetylase Inhibitor Panobinostat (LBH589)

Fredenhagen, Andreas; Kittelmann, Matthias; Oberer, Lukas; Kuhn, Anton; Kühnöl, Jürgen; Délémonté, Thierry; Aichholz, Reiner; Wang, Ping; Atadja, Peter; Shultz, Michael D.

doi:10.1124/dmd.111.043620

Cited by 13 publications

(3 citation statements)

References 31 publications

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“…This assay is ideal for evaluating the efficacy of candidate LRAs in preclinical studies. In this work, we evaluate representative candidates from two promising LRA classes, protein kinase C agonists (PKCa) (14)(15)(16)(17)(18)(19)(20) and histone deacetylase inhibitors (HDACi) (21)(22)(23)(24).…”

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confidence: 99%

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4⁺T Cells from Aviremic Patients

Spivak

Bosque

Balch

et al. 2015

Antimicrob Agents Chemother

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The human immunodeficiency virus type 1 (HIV-1) latent reservoir in resting CD4؉ T cells represents a major barrier to viral eradication. Small compounds capable of latency reversal have not demonstrated uniform responses across in vitro HIV-1 latency cell models. Characterizing compounds that demonstrate latency-reversing activity in resting CD4 ؉ T cells from aviremic patients ex vivo will help inform pilot clinical trials aimed at HIV-1 eradication. We have optimized a rapid ex vivo assay using resting CD4 ؉ T cells from aviremic HIV-1 ؉ patients to evaluate both the bioactivity and latency-reversing potential of candidate latency-reversing agents (LRAs). Using this assay, we characterize the properties of two candidate compounds from promising LRA classes, ingenol 3,20-dibenzoate (a protein kinase C agonist) and panobinostat (a histone deacetylase inhibitor), in cells from HIV-1 ؉ antiretroviral therapy (ART)-treated aviremic participants, including the effects on cellular activation and cytotoxicity. Ingenol induced viral release at levels similar to those of the positive control (CD3/28 receptor stimulation) in cells from a majority of participants and represents an exciting LRA candidate, as it combines a robust viral reactivation potential with a low toxicity profile. At concentrations that blocked histone deacetylation, panobinostat displayed a wide range of potency among participant samples and consistently induced significant levels of apoptosis. The protein kinase C agonist ingenol 3,20-dibenzoate demonstrated significant promise in a rapid ex vivo assay using resting CD4 ؉ T cells from treated HIV-1-positive patients to measure latent HIV-1 reactivation. Durable blockade of viral replication by combinations of antiretroviral drugs has transformed human immunodeficiency virus type 1 (HIV-1) infection from an untreatable, lethal condition characterized by progressive immune deficiency into a chronic, manageable medical problem for the vast majority of patients with access to therapy (1). Despite the ability of antiretroviral therapy (ART) to block ongoing HIV-1 replication and allow for restoration of the circulating CD4ϩ T cell population, HIV-1 eradication does not occur with these drugs due to the presence of long-lived viral reservoirs in resting memory CD4 ϩ T cells(2-4). ART can continuously suppress viral replication for years or even decades; however, patients who stop therapy will develop viremia within a matter of weeks and progress to overt immunodeficiency if ART is not resumed (5). This rebound viremia arises from a minority of cells among the resting memory CD4 ϩ T cell population harboring unexpressed HIV-1 proviral DNA that is stably integrated into the cellular genome (6).The HIV-1 latent reservoir in patients on ART is stable over a period of many years and does not decay significantly during the life span of an infected patient (7). It is generally accepted that eradication of the virus will require elimination of this latent reservoir (8, 9). The absence of specific markers to dist...

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confidence: 99%

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4⁺T Cells from Aviremic Patients

Spivak

Bosque

Balch

et al. 2015

Antimicrob Agents Chemother

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“…human (h) cytochrome P450s (CYPs) co‐expressed in Escherichia coli with rec. h P450‐reductase as described earlier, as well as with two bacterial CYPs . Only the bacterial CYP 102A1 (also called BM3) produced appreciable amounts of oxidation products (Table ; other data are not shown).…”

Section: Methodsmentioning

confidence: 99%

Cladosporin Derivatives Obtained by Biotransformation Provide Guidance for the Focused Derivatization of this Antimalarial Lead Compound

et al. 2018

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Cladosporin, a natural product known for decades, has recently been discovered to display potent and selective antiplasmodial activity by inhibition of lysyl‐tRNA synthetase. It was subjected to a panel of oxidative biotransformations with one fungal and two actinomycetes strains, as well as a triple mutant bacterial CYP102A1, yielding eight, mostly hydroxylated, derivatives. These new compounds covered a wide chemical space and contained two pairs of epimers in the tetrahydropyran ring. Although less potent than the parent compound, all analogues showed activity in a cell‐based synthetase assay, thus demonstrating uptake and on‐target activity in living cells with varying degrees of selectivity for the enzyme lysyl‐tRNA synthetase from Plasmodium falciparum and highlighting sites suitable for synthesis of future cladosporin analogues. Compounds with adjacent hydroxy functions showed different MS/MS fragmentation that can be explained in terms of an, in some cases, regioselective loss of water followed by a retro‐Diels–Alder reaction.

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“…Panobinostat is metabolized by numerous routes, including oxidation, reduction and hydrolysis, the former two largely mediated by CYP3A4 (70-98%) with minor contributions from CYPs 2D6 and 2C19 [24]. All metabolites were future science group Pharmacogenomics & histone deacetylase inhibitors Review much less potent HDIs than parent panobinostat [49]. Because CYP3A metabolizes a plethora of other compounds, the potential for DDIs between panobinostat and CYP3A substrates was assessed.…”

Section: Panobinostatmentioning

confidence: 99%

Pharmacogenomics and Histone Deacetylase Inhibitors

et al. 2016

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The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping.

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Biocatalytic Synthesis and Structure Elucidation of Cyclized Metabolites of the Deacetylase Inhibitor Panobinostat (LBH589)

Cited by 13 publications

References 31 publications

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4⁺T Cells from Aviremic Patients

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4⁺T Cells from Aviremic Patients

Cladosporin Derivatives Obtained by Biotransformation Provide Guidance for the Focused Derivatization of this Antimalarial Lead Compound

Pharmacogenomics and Histone Deacetylase Inhibitors

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Biocatalytic Synthesis and Structure Elucidation of Cyclized Metabolites of the Deacetylase Inhibitor Panobinostat (LBH589)

Cited by 13 publications

References 31 publications

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4+T Cells from Aviremic Patients

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4+T Cells from Aviremic Patients

Cladosporin Derivatives Obtained by Biotransformation Provide Guidance for the Focused Derivatization of this Antimalarial Lead Compound

Pharmacogenomics and Histone Deacetylase Inhibitors

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Product

Resources

About

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4⁺T Cells from Aviremic Patients

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4⁺T Cells from Aviremic Patients