title: Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers.
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.
authors.affiliation: Oncology Drug Discovery, Sanofi Research & Development , 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France.
authors.forename: Victor
authors.initials: V
authors.lastname: Certal
authors.forename: Frank
authors.initials: F
authors.lastname: Halley
authors.forename: Angela
authors.initials: A
authors.lastname: Virone-Oddos
authors.forename: Cécile
authors.initials: C
authors.lastname: Delorme
authors.forename: Andreas
authors.initials: A
authors.lastname: Karlsson
authors.forename: Alexey
authors.initials: A
authors.lastname: Rak
authors.forename: Fabienne
authors.initials: F
authors.lastname: Thompson
authors.forename: Bruno
authors.initials: B
authors.lastname: Filoche-Rommé
authors.forename: Youssef
authors.initials: Y
authors.lastname: El-Ahmad
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Carry
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Abecassis
authors.forename: Pascale
authors.initials: P
authors.lastname: Lejeune
authors.forename: Loic
authors.initials: L
authors.lastname: Vincent
authors.forename: Hélène
authors.initials: H
authors.lastname: Bonnevaux
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Nicolas
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertrand
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marquette
authors.forename: Nadine
authors.initials: N
authors.lastname: Michot
authors.forename: Tsiala
authors.initials: T
authors.lastname: Benard
authors.forename: Peter
authors.initials: P
authors.lastname: Below
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vade
authors.forename: Fabienne
authors.initials: F
authors.lastname: Chatreaux
authors.forename: Gilles
authors.initials: G
authors.lastname: Lebourg
authors.forename: Fabienne
authors.initials: F
authors.lastname: Pilorge
authors.forename: Odile
authors.initials: O
authors.lastname: Angouillant-Boniface
authors.forename: Audrey
authors.initials: A
authors.lastname: Louboutin
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.forename: Laurent
authors.initials: L
authors.lastname: Schio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001583:Benzoxazoles; D007527:Isoenzymes; D011744:Pyrimidinones; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase