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Publication Abstract from PubMed

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 PI3Kbeta 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 PI3Kbeta-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 PI3Kbeta and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kdelta showed key interactions and structural features supporting the observed PI3Kbeta 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.

Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3Kbeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers.,Certal V, Halley F, Virone-Oddos A, Delorme C, Karlsson A, Rak A, Thompson F, Filoche-Romme B, El-Ahmad Y, Carry JC, Abecassis PY, Lejeune P, Vincent L, Bonnevaux H, Nicolas JP, Bertrand T, Marquette JP, Michot N, Benard T, Below P, Vade I, Chatreaux F, Lebourg G, Pilorge F, Angouillant-Boniface O, Louboutin A, Lengauer C, Schio L J Med Chem. 2012 May 2. PMID:22524426^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.