Laura Llauger Bufi

Publications (6)17.95 Total impact

• Article: Identification of a series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as potent smoothened antagonist hedgehog pathway inhibitors.

  Jesus M Ontoria, Laura Llauger Bufi, Caterina Torrisi, Alberto Bresciani, Claudia Giomini, Michael Rowley, Sergio Serafini, Hu Bin, Wu Hao, Christian Steinkühler, Philip Jones
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  ABSTRACT: The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway.
  Bioorganic & medicinal chemistry letters 09/2011; 21(18):5274-82. · 2.65 Impact Factor
• Article: N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists.

  Ester Muraglia, Jesus M Ontoria, Danila Branca, Gabriella Dessole, Alberto Bresciani, Massimiliano Fonsi, Claudio Giuliano, Laura Llauger Bufi, Edith Monteagudo, Maria Cecilia Palumbi, Caterina Torrisi, Michael Rowley, Christian Steinkühler, Philip Jones
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  ABSTRACT: Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies.
  Bioorganic & medicinal chemistry letters 09/2011; 21(18):5283-8. · 2.65 Impact Factor
• Article: Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1).

  Giovanna Pescatore, Danila Branca, Fabrizio Fiore, Olaf Kinzel, Laura Llauger Bufi, Ester Muraglia, Federica Orvieto, Michael Rowley, Carlo Toniatti, Caterina Torrisi, Philip Jones
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  ABSTRACT: Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells.
  Bioorganic & medicinal chemistry letters 02/2010; 20(3):1094-9. · 2.65 Impact Factor
• Article: Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells.

  Federica Ferrigno, Danila Branca, Olaf Kinzel, Samuele Lillini, Laura Llauger Bufi, Edith Monteagudo, Ester Muraglia, Michael Rowley, Carsten Schultz-Fademrecht, Carlo Toniatti, Caterina Torrisi, Philip Jones
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  ABSTRACT: We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.
  Bioorganic & medicinal chemistry letters 11/2009; 20(3):1100-5. · 2.65 Impact Factor
• Article: Discovery of a potent class I selective ketone histone deacetylase inhibitor with antitumor activity in vivo and optimized pharmacokinetic properties.

  Olaf Kinzel, Laura Llauger-Bufi, Giovanna Pescatore, Michael Rowley, Carsten Schultz-Fademrecht, Edith Monteagudo, Massimiliano Fonsi, Odalys Gonzalez Paz, Fabrizio Fiore, Christian Steinkühler, Philip Jones
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  ABSTRACT: The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclinical species, has a clean off-target profile, and is negative in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose.
  Journal of Medicinal Chemistry 06/2009; 52(11):3453-6. · 4.80 Impact Factor
• Article: Synthesis of novel fluorescent probes for the molecular chaperone Hsp90.

  Laura Llauger-Bufi, Sara J Felts, Henri Huezo, Neal Rosen, Gabriela Chiosis
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  ABSTRACT: Heat shock protein 90 (Hsp90) is a molecular chaperone necessary for maintaining oncogenic transformation. There is substantial interest in developing novel agents that bind to the N-terminal of the chaperone. Here we report the synthesis and characterization of two fluorescent Hsp90 inhibitors and probe their use in an Hsp90 fluorescent polarization assay.
  Bioorganic & Medicinal Chemistry Letters 12/2003; 13(22):3975-8. · 2.55 Impact Factor