4AJW

Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3KBeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers

Summary for 4AJW

• Entry DOI: 10.2210/pdb4ajw/pdb
• Related: 2WXE 2WXF 2WXG 2WXH 2WXI 2WXJ 2WXK 2WXL 2WXM 2WXN 2WXO 2WXP 2WXQ 2WXR 2X38
• Descriptor: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM, 2-[(1-methyl-1H-benzimidazol-2-yl)methyl]-6-morpholin-4-ylpyrimidin-4(3H)-one (3 entities in total)
• Functional Keywords: transferase, p110d
• Biological source: MUS MUSCULUS (HOUSE MOUSE)
• Total number of polymer chains: 2
• Total formula weight: 215070.78

Authors

Certal, V.,Halley, F.,Virone-Oddos, A.,Delorme, C.,Karlsson, A.,Rak, A.,Thompson, F.,Filoche-Romme, B.,El-Ahmad, Y.,Carry, J.C.,Abecassis, P.Y.,Lejeune, P.,Bonnevaux, H.,Nicolas, J.P.,Bertrand, T.,Marquette, J.P.,Michot, N.,Benard, T.,Below, P.,Vade, I.,Chatreaux, F.,Lebourg, G.,Pilorge, F.,Angouillant-Boniface, O.,Louboutin, A.,Lengauer, C.,Schio, L. (deposition date: 2012-02-20, release date: 2012-05-16, Last modification date: 2023-12-20)

Primary citation

Certal, V.,Halley, F.,Virone-Oddos, A.,Delorme, C.,Karlsson, A.,Rak, A.,Thompson, F.,Filoche-Romm, B.,El-Ahmad, Y.,Carry, J.C.,Abecassis, P.Y.,Lejeune, P.,Vincent, L.,Bonnevaux, H.,Nicolas, J.P.,Bertrand, T.,Marquette, J.P.,Michot, N.,Benard, T.,Below, P.,Vade, I.,Chatreaux, F.,Lebourg, G.,Pilorge, F.,Angouillant-Boniface, O.,Louboutin, A.,Lengauer, C.,Schio, L.
Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective Pi3Kbeta Inhibitors for the Treatment of Phosphatase and Tensin Homologue (Pten)-Deficient Cancers.
J.Med.Chem., 55:4788-, 2012

PubMed 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.

PubMed: 22524426
DOI: 10.1021/JM300241B

Experimental method

X-RAY DIFFRACTION (2.8 Å)