View source for 4bzn


==Crystal structure of PIM1 in complex with a Pyrrolo(1,2-a)Pyrazinone inhibitor==
<StructureSection load='4bzn' size='340' side='right'caption='[[4bzn]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4bzn]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BZN 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=UGX:N-(2,2-DIMETHYLPROPYL)-2-[1-OXO-7-(THIOPHEN-3-YL)-1,2,3,4-TETRAHYDROPYRROLO[1,2-A]PYRAZIN-4-YL]ACETAMIDE'>UGX</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=4bzn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bzn OCA], [https://pdbe.org/4bzn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bzn RCSB], [https://www.ebi.ac.uk/pdbsum/4bzn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bzn ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PIM1_HUMAN PIM1_HUMAN] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.<ref>PMID:1825810</ref> <ref>PMID:10664448</ref> <ref>PMID:12431783</ref> <ref>PMID:15528381</ref> <ref>PMID:16356754</ref> <ref>PMID:18593906</ref> <ref>PMID:19749799</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.

Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.,Casuscelli F, Ardini E, Avanzi N, Casale E, Cervi G, D'Anello M, Donati D, Faiardi D, Ferguson RD, Fogliatto G, Galvani A, Marsiglio A, Mirizzi DG, Montemartini M, Orrenius C, Papeo G, Piutti C, Salom B, Felder ER Bioorg Med Chem. 2013 Oct 2. pii: S0968-0896(13)00834-1. doi:, 10.1016/j.bmc.2013.09.054. PMID:24139169<ref>PMID:24139169</ref>

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

==See Also==
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
*[[3D structures of pim-1|3D structures of pim-1]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ardini E]]
[[Category: Avanzi N]]
[[Category: Casale E]]
[[Category: Casuscelli F]]
[[Category: Cervi G]]
[[Category: D'Anello M]]
[[Category: Donati D]]
[[Category: Faiardi D]]
[[Category: Felder ER]]
[[Category: Ferguson RD]]
[[Category: Fogliatto G]]
[[Category: Galvani A]]
[[Category: Marsiglio A]]
[[Category: Mirizzi DG]]
[[Category: Montemartini M]]
[[Category: Orrenius C]]
[[Category: Papeo G]]
[[Category: Piutti C]]
[[Category: Salom B]]