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4bfr

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Revision as of 11:46, 5 August 2016

Discovery and Optimization of Pyrimidone Indoline Amide PI3Kbeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers

Structural highlights

4bfr is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:	Phosphatidylinositol-4,5-bisphosphate 3-kinase, with EC number 2.7.1.153
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PK3CB_MOUSE] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(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. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3K in PTEN-deficient cell lines growth and proliferation. These findings supported a scientific rationale for the development of PI3K-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one 7 and the optimization of this new series of active and selective pyrimidone indoline amide PI3K inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin -4-one 28, identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the obtention of the first X-Ray co-crystal structure of p110 with the selective inhibitor compound 28 bound to the ATP site. The non-planar binding mode described herein is consistent with observed SAR for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.

Discovery and Optimization of Pyrimidone Indoline Amide PI3Kss Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers.,Certal V, Carry JC, Halley F, Virone-Oddos A, Thompson F, Filoche-Romme B, El-Ahmad Y, Karlsson A, Charrier V, Delorme C, Rak A, Abecassis PY, Amara C, Vincent L, Bonnevaux H, Nicolas JP, Mathieu M, Bertrand T, Marquette JP, Michot N, Benard T, Perrin MA, Lemaitre O, Guerif S, Perron S, Monget S, Gruss-Leleu F, Doerflinger G, Guizani H, Brollo M, Delbarre L, Bertin L, Richepin P, Loyau V, Garcia-Echeverria C, Lengauer C, Schio L J Med Chem. 2014 Jan 4. PMID:24387221^[7]

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

References

↑ Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, Zhao JJ. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature. 2008 Aug 7;454(7205):776-9. doi: 10.1038/nature07091. Epub 2008 Jun 25. PMID:18594509 doi:http://dx.doi.org/10.1038/nature07091
↑ Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJ, Okkenhaug K, Vanhaesebroeck B. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8292-7. doi:, 10.1073/pnas.0707761105. Epub 2008 Jun 10. PMID:18544649 doi:http://dx.doi.org/10.1073/pnas.0707761105
↑ Canobbio I, Stefanini L, Cipolla L, Ciraolo E, Gruppi C, Balduini C, Hirsch E, Torti M. Genetic evidence for a predominant role of PI3Kbeta catalytic activity in ITAM- and integrin-mediated signaling in platelets. Blood. 2009 Sep 3;114(10):2193-6. doi: 10.1182/blood-2009-03-208074. Epub 2009, Jun 10. PMID:19515725 doi:http://dx.doi.org/10.1182/blood-2009-03-208074
↑ Martin V, Guillermet-Guibert J, Chicanne G, Cabou C, Jandrot-Perrus M, Plantavid M, Vanhaesebroeck B, Payrastre B, Gratacap MP. Deletion of the p110beta isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo. Blood. 2010 Mar 11;115(10):2008-13. doi: 10.1182/blood-2009-04-217224. Epub 2010 , Jan 11. PMID:20065293 doi:http://dx.doi.org/10.1182/blood-2009-04-217224
↑ Schoenwaelder SM, Ono A, Nesbitt WS, Lim J, Jarman K, Jackson SP. Phosphoinositide 3-kinase p110 beta regulates integrin alpha IIb beta 3 avidity and the cellular transmission of contractile forces. J Biol Chem. 2010 Jan 22;285(4):2886-96. doi: 10.1074/jbc.M109.029132. Epub 2009 , Nov 23. PMID:19940148 doi:http://dx.doi.org/10.1074/jbc.M109.029132
↑ Dou Z, Chattopadhyay M, Pan JA, Guerriero JL, Jiang YP, Ballou LM, Yue Z, Lin RZ, Zong WX. The class IA phosphatidylinositol 3-kinase p110-beta subunit is a positive regulator of autophagy. J Cell Biol. 2010 Nov 15;191(4):827-43. doi: 10.1083/jcb.201006056. Epub 2010 Nov, 8. PMID:21059846 doi:http://dx.doi.org/10.1083/jcb.201006056
↑ Certal V, Carry JC, Halley F, Virone-Oddos A, Thompson F, Filoche-Romme B, El-Ahmad Y, Karlsson A, Charrier V, Delorme C, Rak A, Abecassis PY, Amara C, Vincent L, Bonnevaux H, Nicolas JP, Mathieu M, Bertrand T, Marquette JP, Michot N, Benard T, Perrin MA, Lemaitre O, Guerif S, Perron S, Monget S, Gruss-Leleu F, Doerflinger G, Guizani H, Brollo M, Delbarre L, Bertin L, Richepin P, Loyau V, Garcia-Echeverria C, Lengauer C, Schio L. Discovery and Optimization of Pyrimidone Indoline Amide PI3Kss Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers. J Med Chem. 2014 Jan 4. PMID:24387221 doi:http://dx.doi.org/10.1021/jm401642q

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4bfr"

@@ Line 1: / Line 1: @@
 ==Discovery and Optimization of Pyrimidone Indoline Amide PI3Kbeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers==
 <StructureSection load='4bfr' size='340' side='right' caption='[[4bfr]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=J82:2-[2-(2-METHYL-2,3-DIHYDRO-INDOL-1-YL)-2-OXO-ETHYL]-6-MORPHOLIN-4-YL-3H-PYRIMIDIN-4-ONE'>J82</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4bfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bfr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bfr RCSB], [http://www.ebi.ac.uk/pdbsum/4bfr PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4bfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bfr OCA], [http://pdbe.org/4bfr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bfr RCSB], [http://www.ebi.ac.uk/pdbsum/4bfr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bfr ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4bfr" style="background-color:#fffaf0;"></div>
 ==See Also==

4bfr

From Proteopedia

Revision as of 11:46, 5 August 2016

Discovery and Optimization of Pyrimidone Indoline Amide PI3Kbeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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