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, Pierre Yves Abecassis, Pascale Lejeune, Loic Vincent, Hélène Bonnevaux, Jean Paul Nicolas, Thomas Bertrand, Jean Pierre Marquette, Nadine Michot, Tsiala Benard, Peter BelowIsabelle Vade, Fabienne Chatreaux, Gilles Lebourg, Fabienne Pilorge, Odile Angouillant-Boniface, Audrey Louboutin, Christoph Lengauer, Laurent Schio

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4788-4805
Number of pages18
JournalJournal of Medicinal Chemistry
Volume55
Issue number10
DOIs
StatePublished - May 24 2012
Externally publishedYes

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Benzoxazoles
Pyrimidinones
1-Phosphatidylinositol 4-Kinase
Phosphoric Monoester Hydrolases
Neoplasms
Protein Isoforms
SCID Mice
Pharmaceutical Chemistry
Tensins
benzimidazole
Heterografts
Carcinogenesis
Phosphotransferases
Pharmacokinetics
X-Rays
Clinical Trials

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. / Certal, Victor; Halley, Frank; Virone-Oddos, Angela; Delorme, Cécile; Karlsson, Andreas; Rak, Alexey; Thompson, Fabienne; Filoche-Rommé, Bruno; El-Ahmad, Youssef; Carry, Jean Christophe; Abecassis, Pierre Yves; Lejeune, Pascale; Vincent, Loic; Bonnevaux, Hélène; Nicolas, Jean Paul; Bertrand, Thomas; Marquette, Jean Pierre; Michot, Nadine; Benard, Tsiala; Below, Peter; Vade, Isabelle; Chatreaux, Fabienne; Lebourg, Gilles; Pilorge, Fabienne; Angouillant-Boniface, Odile; Louboutin, Audrey; Lengauer, Christoph; Schio, Laurent.

In: Journal of Medicinal Chemistry, Vol. 55, No. 10, 24.05.2012, p. 4788-4805.

Research output: Contribution to journalArticle

Certal, V, Halley, F, Virone-Oddos, A, Delorme, C, Karlsson, A, Rak, A, Thompson, F, Filoche-Rommé, 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 2012, 'Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers', Journal of Medicinal Chemistry, vol. 55, no. 10, pp. 4788-4805. https://doi.org/10.1021/jm300241b
Certal, Victor ; Halley, Frank ; Virone-Oddos, Angela ; Delorme, Cécile ; Karlsson, Andreas ; Rak, Alexey ; Thompson, Fabienne ; Filoche-Rommé, Bruno ; El-Ahmad, Youssef ; Carry, Jean Christophe ; Abecassis, Pierre Yves ; Lejeune, Pascale ; Vincent, Loic ; Bonnevaux, Hélène ; Nicolas, Jean Paul ; Bertrand, Thomas ; Marquette, Jean Pierre ; Michot, Nadine ; Benard, Tsiala ; Below, Peter ; Vade, Isabelle ; Chatreaux, Fabienne ; Lebourg, Gilles ; Pilorge, Fabienne ; Angouillant-Boniface, Odile ; Louboutin, Audrey ; Lengauer, Christoph ; Schio, Laurent. / Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 10. pp. 4788-4805.
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AU - Rak, Alexey

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AU - Below, Peter

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AU - Pilorge, Fabienne

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