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4mbi

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{{STRUCTURE_4mbi| PDB=4mbi | SCENE= }}
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==Discovery of Pyrazolo[1,5a]pyrimidine-based Pim1 Inhibitors==
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===Discovery of Pyrazolo[1,5a]pyrimidine-based Pim1 Inhibitors===
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<StructureSection load='4mbi' size='340' side='right' caption='[[4mbi]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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{{ABSTRACT_PUBMED_24091081}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4mbi]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MBI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MBI FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=26K:N,N-DIMETHYL-N-[3-(1H-PYRAZOL-4-YL)PYRAZOLO[1,5-A]PYRIMIDIN-5-YL]ETHANE-1,2-DIAMINE'>26K</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mbl|4mbl]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
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<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=4mbi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mbi OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mbi RCSB], [http://www.ebi.ac.uk/pdbsum/4mbi PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The synthesis and hit-to-lead SAR development from a pyrazolo[1,5-a]pyrimidine-derived hit 5 to the identification of a series of potent, pan-Pim inhibitors such as 11j are described.
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==Function==
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Discovery of pyrazolo[1,5-a]pyrimidine-based Pim inhibitors: A template-based approach.,Dwyer MP, Keertikar K, Paruch K, Alvarez C, Labroli M, Poker C, Fischmann TO, Mayer-Ezell R, Bond R, Wang Y, Azevedo R, Guzi TJ Bioorg Med Chem Lett. 2013 Nov 15;23(22):6178-82. doi:, 10.1016/j.bmcl.2013.08.110. Epub 2013 Sep 7. PMID:24091081<ref>PMID:24091081</ref>
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[[http://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>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4mbi]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MBI OCA].
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</div>
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:024091081</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Azevedo, R.]]
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[[Category: Azevedo, R]]
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[[Category: Fischmann, T O.]]
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[[Category: Fischmann, T O]]
[[Category: Kinase]]
[[Category: Kinase]]
[[Category: Transferase-transferase inhibitor complex]]
[[Category: Transferase-transferase inhibitor complex]]

Revision as of 15:24, 21 December 2014

Discovery of Pyrazolo[1,5a]pyrimidine-based Pim1 Inhibitors

4mbi, resolution 2.30Å

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