- COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF TUMORS
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The present invention relates to compounds of Formula (Ia) or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, stereoisomers thereof. It further discloses a pharmaceutical composition comprising compounds of Formula (Ia) and the use of compounds of Formula (Ib), in particular for the use in the treatment of diseases or disorders wherein disrupting Rad51-BRCA2 interaction is beneficial.
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Page/Page column 60-61; 63-64
(2021/06/22)
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- Synthetic Lethality in Pancreatic Cancer: Discovery of a New RAD51-BRCA2 Small Molecule Disruptor That Inhibits Homologous Recombination and Synergizes with Olaparib
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Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.
- Bagnolini, Greta,Milano, Domenico,Manerba, Marcella,Schipani, Fabrizio,Ortega, Jose Antonio,Gioia, Dario,Falchi, Federico,Balboni, Andrea,Farabegoli, Fulvia,De Franco, Francesca,Robertson, Janet,Pellicciari, Roberto,Pallavicini, Isabella,Peri, Sebastiano,Minucci, Saverio,Girotto, Stefania,Di Stefano, Giuseppina,Roberti, Marinella,Cavalli, Andrea
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p. 2588 - 2619
(2020/03/05)
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- Quinolinones as Inhibitors of Translation Initiation Complex
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Provided herein are compounds and pharmaceutical compositions comprising quinolinones. The quinolinones and compositions thereof are useful as eukaryotic translation initiation factor 4F (eIF4F) complex modulators.
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Paragraph 0628
(2018/03/25)
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- METHODS AND COMPOSITIONS FOR INHIBITION OF BROMODOMAIN-CONTAINING PROTEINS
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The present invention relates to compounds that bind to and otherwise modulate the activity of bromodomain-containing proteins, to processes for preparing these compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds for treating a wide variety of conditions and disorders.
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Page/Page column 75
(2014/10/15)
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- Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists
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Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit selectivity for GluN2C- and GluN2D-containing receptors over GluN2A- and GluN2B-containing receptors. Several members of this class inhibit NMDA receptor responses in the nanomolar range and are more than 50-fold selective over GluN1/GluN2A and GluN1/GluN2B NMDA receptors, as well as AMPA, kainate, GABA, glycine, nicotinic, serotonin, and purinergic receptors. Analysis of the purified enantiomers of one of the more potent and selective compounds shows that the S-enantiomer is both more potent and more selective than the R-enantiomer. The S-enantiomer had an IC 50 of 0.17-0.22 μM at GluN2D- and GluN2C-containing receptors, respectively, and showed over 70-fold selectivity over other NMDA receptor subunits. The subunit selectivity of this class of compounds should be useful in defining the role of GluN2C- and GluN2D-containing receptors in specific brain circuits in both physiological and pathophysiological conditions.
- Acker, Timothy M.,Khatri, Alpa,Vance, Katie M.,Slabber, Cathryn,Bacsa, John,Snyder, James P.,Traynelis, Stephen F.,Liotta, Dennis C.
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supporting information
p. 6434 - 6456
(2013/09/23)
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- Synthesis and SAR studies of dual AKT/NF-κB inhibitors against melanoma
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The protein Kinase B alpha (AKT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways are central regulators of cellular signaling events at the basis of tumor development and progression. Both pathways are often up-regulated in different tumor types including melanoma. We recently reported the identification of compound 1 (BI-69A11) as inhibitor of the AKT and the NF-κB pathways. Here, we describe SAR studies that led to novel fluorinated derivatives with increased cellular potency, reflected in efficient inhibition of AKT and IKKs. Selected compounds demonstrated effective toxicity on melanoma, breast, and prostate cell lines. Finally, a representative derivative showed promising efficacy in an in vivo melanoma xenograft model. We describe SAR studies that led to compound 42 as a potent cellular inhibitor of phosphorylation of AKT1-3 and the NF-κB pathway in melanoma, breast, and prostate cell lines and showed remarkable efficacy in an in vivo melanoma xenograft model with the drug administered orally.
- Barile, Elisa,De, Surya K.,Feng, Yongmei,Chen, Vida,Yang, Li,Ronai, Ze'ev,Pellecchia, Maurizio
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p. 520 - 533
(2013/11/06)
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- Solvent-free synthesis and antibacterial studies of some quinolinones
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Solvent-free, microwave-induced condensation of 2-aminoaryl alkyl ketones and ethyl 3-oxobutanoate in the presence of amberlite Na sr1L gave quinolinones in high yield when compared to other catalysts. Further, N-alkylation of the quinolinones was carried
- Subashini, Radhakrishnan,Khan, Fazlur-Rahman Nawaz
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experimental part
p. 485 - 489
(2012/06/16)
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- Microwave assisted Friedlaender condensation: A comparative study of conventional versus microwave mediated solvent-free methodologies
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4-Arylquinolines have been prepared by Friedlaender reaction with acid as a catalyst and without the catalyst under microwave assisted solvent-free conditions and compared with classical heating.
- Agrawal,Joshipura, Hardik M.
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p. 1649 - 1652
(2007/10/03)
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