Bruno Filoche-Rommé

Publications (2)7.45 Total impact

• Article: Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors.

  Victor Certal, Frank Halley, Angela Virone-Oddos, Fabienne Thompson, Bruno Filoche-Rommé, Youssef El-Ahmad, Jean-Christophe Carry, Cécile Delorme, Andreas Karlsson, Pierre-Yves Abecassis, [......], Renaud Morales, Nadine Michot, Isabelle Vade, Audrey Louboutin, Sébastien Perron, Gilles Doerflinger, Bernadette Tric, Sylvie Monget, Christoph Lengauer, Laurent Schio
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  ABSTRACT: From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.
  Bioorganic & medicinal chemistry letters 08/2012; 22(20):6381-4. · 2.65 Impact Factor
• Article: Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers.

  Victor Certal, Frank Halley, Angela Virone-Oddos, Cécile Delorme, Andreas Karlsson, Alexey Rak, Fabienne Thompson, Bruno Filoche-Rommé, Youssef El-Ahmad, Jean-Christophe Carry, [......], Tsiala Benard, Peter Below, Isabelle Vade, Fabienne Chatreaux, Gilles Lebourg, Fabienne Pilorge, Odile Angouillant-Boniface, Audrey Louboutin, Christoph Lengauer, Laurent Schio
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  ABSTRACT: Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kβ and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kβ isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.
  Journal of Medicinal Chemistry 04/2012; 55(10):4788-805. · 4.80 Impact Factor