View source for 4ajw


==Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3KBeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers==
<StructureSection load='4ajw' size='340' side='right'caption='[[4ajw]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4ajw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AJW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AJW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VWN:2-[(1-METHYL-1H-BENZIMIDAZOL-2-YL)METHYL]-6-MORPHOLIN-4-YLPYRIMIDIN-4(3H)-ONE'>VWN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ajw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ajw OCA], [https://pdbe.org/4ajw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ajw RCSB], [https://www.ebi.ac.uk/pdbsum/4ajw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ajw ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PK3CD_MOUSE PK3CD_MOUSE] Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function.<ref>PMID:12130661</ref> <ref>PMID:12235209</ref> <ref>PMID:15496927</ref> <ref>PMID:16116162</ref> <ref>PMID:18259608</ref> <ref>PMID:18809712</ref> <ref>PMID:19297623</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:22524426</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4ajw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Phosphoinositide 3-kinase 3D structures|Phosphoinositide 3-kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Abecassis PY]]
[[Category: Angouillant-Boniface O]]
[[Category: Below P]]
[[Category: Benard T]]
[[Category: Bertrand T]]
[[Category: Bonnevaux H]]
[[Category: Carry JC]]
[[Category: Certal V]]
[[Category: Chatreaux F]]
[[Category: Delorme C]]
[[Category: El-Ahmad Y]]
[[Category: Filoche-Romme B]]
[[Category: Halley F]]
[[Category: Karlsson A]]
[[Category: Lebourg G]]
[[Category: Lejeune P]]
[[Category: Lengauer C]]
[[Category: Louboutin A]]
[[Category: Marquette JP]]
[[Category: Michot N]]
[[Category: Nicolas JP]]
[[Category: Pilorge F]]
[[Category: Rak A]]
[[Category: Schio L]]
[[Category: Thompson F]]
[[Category: Vade I]]
[[Category: Virone-Oddos A]]