Olivier Venier - Academia.edu (original) (raw)

Papers by Olivier Venier

Chemical Communications, Jun 28, 2022

Le traitement des n-boc aminoalcools par le chlorure de tosyle conduit au moyen d'une reactio... more Le traitement des n-boc aminoalcools par le chlorure de tosyle conduit au moyen d'une reaction de cyclisation aux oxazolidin-2-ones correspondantes. Une heterocyclisation similaire est observee avec des analogues soufres des carbamates : les dithiocarbamates. Un effet thorpe-ingold peu courant est observe et est etudie au moyen de calculs am1. Par ailleurs, des epoxyoxazolidines enantiopures sont obtenues en deux etapes a partir d'alcenyloxazolidines. L'etape-cle de ces syntheses est une reaction de cyclocarbamation. L'ouverture de ces epoxydes au moyen de differents nucleophiles (azoture, cuprates) permet apres plusieurs fonctionnalisations d'acceder a des composes dont certains possedent des proprietes biologiques interessantes : des pheromones, un stereoisomere anti de la chaine lateral du taxol ainsi qu'un isostere de type hydroxyethylamine. La reaction de cyclocarbamation ainsi que l'ouverture nucleophile des epoxyoxazolidines est totalement regiosel...

Cancer Research, 2020

The HIPPO pathway plays an important role in cancer progression and one of its essential componen... more The HIPPO pathway plays an important role in cancer progression and one of its essential components are the transcription factor proteins from the TEAD family. The TEAD family consists of 4 different family members (TEAD1-TEAD4) who modulate gene expression through the interaction with co-activator proteins such as YAP1 and TAZ. Recent studies have shown that TEADs are partially palmitoylated. Activity and stability of TEAD proteins are regulated by this modification. Here, we attempt to better understand the palmitoylation status of TEAD proteins in cells. In a first step, we have developed LC/MS/MS-based assays for the detection of palmitoylated TEAD peptides using recombinant TEAD1 protein. Subsequently, we have set out to analyze endogenous TEAD proteins using YAP1 activated malignant mesothelioma H2052 tumor cells. H2052 tumor cells express preferentially TEAD1 protein. TEAD1 was immunoprecipitated from H2052 tumor cells and subjected to peptidic digest and LC/MS/MS analysis. P...

The invention relates phenoxypropanolamines of formula (I) (CF DRAWING IN BOPI) wherein R1 is hyd... more The invention relates phenoxypropanolamines of formula (I) (CF DRAWING IN BOPI) wherein R1 is hydrogen, -S (O) z (C1-C4) Alk group, a group -NHSO2 - (C1 -C4) Alk, NHCO (C1-C4) alk m and n are independently 0, 1 or 2; R2 and R3 independently represent hydrogen, an aromatic or heteroaromatic ring, unsubstituted or substituted with a group R4, an aralkyl or heteroaralkyl group, unsubstituted or substituted with a group R4; R2 and R3 are not simultaneously represent hydrogen; or R2 and R3 together may represent a saturated or unsaturated ring having 3 to 8 atoms; z is 1 or 2; R4 represents hydrogen, -CO (C1 -C4) Alk group or an -NHSO2 - (C1 -C4) Alk; a (C1 -C4) Alk group, a (C1 - C4) alkoxy, halogen, -COOH, -COO (C1 -C4) Alk, -CN, - CONR3 R4, -NO2, -SO2 NH2, -NHSO2 ( C 1 -C 4) Alk group; and salts or solvates thereof. The compounds have agonist activity vis-a-vis the 3-adrenergic receptors.

Cancer Research, 2021

The HIPPO pathway plays an important role in cancer progression and among its essential component... more The HIPPO pathway plays an important role in cancer progression and among its essential components are the transcription factor proteins from the TEAD family. The TEAD family consists of 4 different members (TEAD1-TEAD4) who modulate gene expression through the interaction with co-activator proteins such as YAP1 and TAZ. Recent studies have shown that the central pocket of TEAD could be an alternative druggable approach for inhibiting YAP1. However, until recently, the irreversible binding mechanism of such a compound in living cells was not clearly established. Here, we report a mass spectrometry-based approach to demonstrate and quantitatively assess the target occupancy of TEADs covalent inhibitors both in vitro cellular and ex vivo tumor models. Applying our method to compounds from different chemical series confirmed that these inhibitors modulate the TEAD central pocket protein in cell cultures and led us to quantify their target occupancy for all TEADs expressed in our cellul...

L'invention concerne des derives d'urees de tropane de formule (I) et leur application co... more L'invention concerne des derives d'urees de tropane de formule (I) et leur application comme modulateurs de l'activite de la 11β-hodroxysteroide dehydrogenose type 1 (11βHSD1)

Current Protocols in Molecular Biology, 2020

High‐throughput screening is one of the pillars of drug development. Unbiased transcriptome profi... more High‐throughput screening is one of the pillars of drug development. Unbiased transcriptome profiling is now widely used for a deeper understanding of a drug's mechanisms of action, off target effects, and cytotoxicity. Although currently available high‐throughput RNA‐Seq (HT RNA‐Seq) methods such as PLATE‐Seq, DRUG‐Seq, and BRB‐Seq serve these purposes, the inherent nature of these methods does not allow sample‐wise sequencing library quality control. Here, we describe an HTR method called High‐throughput CellulAr RNA Sequencing (HiCAR‐Seq). HiCAR‐Seq was optimized to work directly on cultured cells (as little as 1,000 cells) or 10 ng of total RNA. HiCAR‐Seq involves reverse transcription from cultured cells or total RNA using oligo‐dT primers followed by the PCR amplification of full‐length cDNAs using sample‐specific barcode primers in individual plate wells. Amplification of cDNA from every sample can be verified using Bioanalyzer. This step not only reveals cDNA amplification but also provides greater precision for pooling equal concentrations of cDNA from different samples. A single pooled cDNA library is made suitable for sequencing on Illumina sequencers using a tagmentation kit. Because HiCAR‐Seq targets a small region at the 3′ of the mRNAs, as little as 3 to 4 million reads/sample are enough to infer changes in gene expression in human or mouse cells. We believe that HiCAR‐Seq represents a robust and competitive addition to the existing set of transcriptome‐based high‐throughput screening methods. © 2020 Wiley Periodicals LLC.

Cancer Research, 2020

YAP1 and TEAD are transcriptional regulators involved in organ size control and cell proliferatio... more YAP1 and TEAD are transcriptional regulators involved in organ size control and cell proliferation. Aberrant activation of YAP1 has been reported for multiple tumor types and inhibiting the interaction of YAP1 with its partner protein TEAD is thought to be a means of targeting aberrant YAP1 activity. In order to identify small molecule inhibitors of YAP1 interaction with TEAD, we have performed a fragment-based-screening looking for ligands binding to TEAD at its interface with YAP1 (TEAD pocket S3). We have employed three techniques for fragment screening (NMR, SPR, DSF) and have cross tested positive hits identified by one technique with the respective orthogonal method. Using this strategy on Sanofi proprietary fragment libraries, three different fragment series have been identified. X-Ray co-structures with TEAD have been obtained for all three fragment series confirming binding to the S3 pocket of TEAD. Binding mode determination by X-Ray crystallography has set the stage for s...

Bioorganic & Medicinal Chemistry Letters, 2016

Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a ... more Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.

Bioorganic & Medicinal Chemistry Letters, 2012

Cells, 2021

The Hippo pathway is an evolutionary conserved signaling network that regulates essential process... more The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to hyperproliferation, resistance to chemotherapy, compensation for mKRAS and tumor immune evasion. As the terminal effectors of the Hippo pathway, the transcriptional coactivators YAP1/TAZ and the transcription factors TEAD1–4 present exciting opportunities to pharmacologically modulate the Hippo biology in cancer settings, inflammation and regenerative medicine. This review will provide an overview of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein–protein interaction (PPI) with TEAD1–4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP1/TAZ–TEAD-dependent transcription in cancer.

Chemical Communications, Jun 28, 2022

Le traitement des n-boc aminoalcools par le chlorure de tosyle conduit au moyen d'une reactio... more Le traitement des n-boc aminoalcools par le chlorure de tosyle conduit au moyen d'une reaction de cyclisation aux oxazolidin-2-ones correspondantes. Une heterocyclisation similaire est observee avec des analogues soufres des carbamates : les dithiocarbamates. Un effet thorpe-ingold peu courant est observe et est etudie au moyen de calculs am1. Par ailleurs, des epoxyoxazolidines enantiopures sont obtenues en deux etapes a partir d'alcenyloxazolidines. L'etape-cle de ces syntheses est une reaction de cyclocarbamation. L'ouverture de ces epoxydes au moyen de differents nucleophiles (azoture, cuprates) permet apres plusieurs fonctionnalisations d'acceder a des composes dont certains possedent des proprietes biologiques interessantes : des pheromones, un stereoisomere anti de la chaine lateral du taxol ainsi qu'un isostere de type hydroxyethylamine. La reaction de cyclocarbamation ainsi que l'ouverture nucleophile des epoxyoxazolidines est totalement regiosel...

Cancer Research, 2020

The HIPPO pathway plays an important role in cancer progression and one of its essential componen... more The HIPPO pathway plays an important role in cancer progression and one of its essential components are the transcription factor proteins from the TEAD family. The TEAD family consists of 4 different family members (TEAD1-TEAD4) who modulate gene expression through the interaction with co-activator proteins such as YAP1 and TAZ. Recent studies have shown that TEADs are partially palmitoylated. Activity and stability of TEAD proteins are regulated by this modification. Here, we attempt to better understand the palmitoylation status of TEAD proteins in cells. In a first step, we have developed LC/MS/MS-based assays for the detection of palmitoylated TEAD peptides using recombinant TEAD1 protein. Subsequently, we have set out to analyze endogenous TEAD proteins using YAP1 activated malignant mesothelioma H2052 tumor cells. H2052 tumor cells express preferentially TEAD1 protein. TEAD1 was immunoprecipitated from H2052 tumor cells and subjected to peptidic digest and LC/MS/MS analysis. P...

The invention relates phenoxypropanolamines of formula (I) (CF DRAWING IN BOPI) wherein R1 is hyd... more The invention relates phenoxypropanolamines of formula (I) (CF DRAWING IN BOPI) wherein R1 is hydrogen, -S (O) z (C1-C4) Alk group, a group -NHSO2 - (C1 -C4) Alk, NHCO (C1-C4) alk m and n are independently 0, 1 or 2; R2 and R3 independently represent hydrogen, an aromatic or heteroaromatic ring, unsubstituted or substituted with a group R4, an aralkyl or heteroaralkyl group, unsubstituted or substituted with a group R4; R2 and R3 are not simultaneously represent hydrogen; or R2 and R3 together may represent a saturated or unsaturated ring having 3 to 8 atoms; z is 1 or 2; R4 represents hydrogen, -CO (C1 -C4) Alk group or an -NHSO2 - (C1 -C4) Alk; a (C1 -C4) Alk group, a (C1 - C4) alkoxy, halogen, -COOH, -COO (C1 -C4) Alk, -CN, - CONR3 R4, -NO2, -SO2 NH2, -NHSO2 ( C 1 -C 4) Alk group; and salts or solvates thereof. The compounds have agonist activity vis-a-vis the 3-adrenergic receptors.

Cancer Research, 2021

The HIPPO pathway plays an important role in cancer progression and among its essential component... more The HIPPO pathway plays an important role in cancer progression and among its essential components are the transcription factor proteins from the TEAD family. The TEAD family consists of 4 different members (TEAD1-TEAD4) who modulate gene expression through the interaction with co-activator proteins such as YAP1 and TAZ. Recent studies have shown that the central pocket of TEAD could be an alternative druggable approach for inhibiting YAP1. However, until recently, the irreversible binding mechanism of such a compound in living cells was not clearly established. Here, we report a mass spectrometry-based approach to demonstrate and quantitatively assess the target occupancy of TEADs covalent inhibitors both in vitro cellular and ex vivo tumor models. Applying our method to compounds from different chemical series confirmed that these inhibitors modulate the TEAD central pocket protein in cell cultures and led us to quantify their target occupancy for all TEADs expressed in our cellul...

L'invention concerne des derives d'urees de tropane de formule (I) et leur application co... more L'invention concerne des derives d'urees de tropane de formule (I) et leur application comme modulateurs de l'activite de la 11β-hodroxysteroide dehydrogenose type 1 (11βHSD1)

Current Protocols in Molecular Biology, 2020

High‐throughput screening is one of the pillars of drug development. Unbiased transcriptome profi... more High‐throughput screening is one of the pillars of drug development. Unbiased transcriptome profiling is now widely used for a deeper understanding of a drug's mechanisms of action, off target effects, and cytotoxicity. Although currently available high‐throughput RNA‐Seq (HT RNA‐Seq) methods such as PLATE‐Seq, DRUG‐Seq, and BRB‐Seq serve these purposes, the inherent nature of these methods does not allow sample‐wise sequencing library quality control. Here, we describe an HTR method called High‐throughput CellulAr RNA Sequencing (HiCAR‐Seq). HiCAR‐Seq was optimized to work directly on cultured cells (as little as 1,000 cells) or 10 ng of total RNA. HiCAR‐Seq involves reverse transcription from cultured cells or total RNA using oligo‐dT primers followed by the PCR amplification of full‐length cDNAs using sample‐specific barcode primers in individual plate wells. Amplification of cDNA from every sample can be verified using Bioanalyzer. This step not only reveals cDNA amplification but also provides greater precision for pooling equal concentrations of cDNA from different samples. A single pooled cDNA library is made suitable for sequencing on Illumina sequencers using a tagmentation kit. Because HiCAR‐Seq targets a small region at the 3′ of the mRNAs, as little as 3 to 4 million reads/sample are enough to infer changes in gene expression in human or mouse cells. We believe that HiCAR‐Seq represents a robust and competitive addition to the existing set of transcriptome‐based high‐throughput screening methods. © 2020 Wiley Periodicals LLC.

Cancer Research, 2020

YAP1 and TEAD are transcriptional regulators involved in organ size control and cell proliferatio... more YAP1 and TEAD are transcriptional regulators involved in organ size control and cell proliferation. Aberrant activation of YAP1 has been reported for multiple tumor types and inhibiting the interaction of YAP1 with its partner protein TEAD is thought to be a means of targeting aberrant YAP1 activity. In order to identify small molecule inhibitors of YAP1 interaction with TEAD, we have performed a fragment-based-screening looking for ligands binding to TEAD at its interface with YAP1 (TEAD pocket S3). We have employed three techniques for fragment screening (NMR, SPR, DSF) and have cross tested positive hits identified by one technique with the respective orthogonal method. Using this strategy on Sanofi proprietary fragment libraries, three different fragment series have been identified. X-Ray co-structures with TEAD have been obtained for all three fragment series confirming binding to the S3 pocket of TEAD. Binding mode determination by X-Ray crystallography has set the stage for s...

Bioorganic & Medicinal Chemistry Letters, 2016

Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a ... more Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.

Bioorganic & Medicinal Chemistry Letters, 2012

Cells, 2021

The Hippo pathway is an evolutionary conserved signaling network that regulates essential process... more The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to hyperproliferation, resistance to chemotherapy, compensation for mKRAS and tumor immune evasion. As the terminal effectors of the Hippo pathway, the transcriptional coactivators YAP1/TAZ and the transcription factors TEAD1–4 present exciting opportunities to pharmacologically modulate the Hippo biology in cancer settings, inflammation and regenerative medicine. This review will provide an overview of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein–protein interaction (PPI) with TEAD1–4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP1/TAZ–TEAD-dependent transcription in cancer.